Phenyl-lower-alkyl piperidines and pyrrolidines

ABSTRACT

N-{2, 3- and 4-[R 1  -(phenyl)-C(═X)]-phenyl-loweralkyl} amines, useful as anti-inflammatory agents, are prepared either by reduction of 2-, 3- or 4-[R 1  -(phenyl)CO]-phenyl-lower-alkanoylamines, which are also useful as anti-inflammatory agents; by benzoylating a phenyl-loweralkylamine; by reaction of a 2-, 3- or 4-lithiophenyl-loweralkylamine with a R 1  -(phenyl)-carboxaldehyde, a R 1  -(phenyl)-lower-alkyl ketone or a R 1  -(phenyl)-carbonitrile; by reaction of a 2-, 3- or 4-[R 1  -(phenyl)-CO]-phenyl-lower-alkyl tosylate with an appropriate amine; or by transformations involving manipulations of a carbonyl or carbinol group.

RELATED APPLICATIONS

This is a division of my copending application Ser. No. 121,836, filedFeb. 15, 1980, now U.S. Pat. No. 4,308,382, patented Dec. 29, 1981,which is a continuation-in-part of application Ser. No. 72,067, filedSept. 4, 1979, abandoned July 18, 1980, which is a division ofapplication Ser. No. 902,569, filed May 3, 1978, and now U.S. Pat. No.4,216,326, patented Aug. 5, 1980, which in turn is acontinuation-in-part of application Ser. No. 813,167, filed July 5,1977, abandoned May 5, 1978, which in turn is a continuation-in-part ofapplication Ser. No. 641,511, filed Dec. 17, 1975, and now U.S. Pat. No.4,069,256, patented Jan. 17, 1978, which in turn is acontinuation-in-part of application Ser. No. 542,553, filed Jan. 20,1975, abandoned Jan. 12, 1976.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

This invention relates to N-{2-, 3- and 4-[R₁(phenyl)-C(═X)]-phenyl-lower-alkyl} amines useful as anti-inflammatoryagents.

(b) Description of the Prior Art

A very large class of organic compounds of widely diverse structuraltypes are known to be useful as anti-inflammatory agents, but many ofsuch anti-inflammatory agents are acidic, for example,α-(3-benzoylphenyl)propionic acid, known generically as ketoprofen(British Pat. No. 1,164,585, published Sept. 17, 1969). Such acidicagents are often irritating, and in some cases are ulcerogenic, to thegastric mucosa when administered orally. There is thus a great need foranti-inflammatory agents, for example compounds having a basic aminefunction, which might be expected to be non-irritating to the gastricmucosa. Although the chemical literature describes numerous types ofamine-substituted compounds asserted to have anti-inflammatory activity[see for example U.S. Pat. Nos. 3,770,748, patented Nov. 6, 1973 and3,803,127, patented Apr. 9, 1974 (N-phenylpolymethyleneimines); U.S.Pat. Nos. 3,772,311, patented Nov. 13, 1973 and 3,773,772, patented Nov.20, 1973 (polymethyleneimino-lower-alkanoylpyrazoles); U.S. Pat. No.3,773,944, patented Nov. 20, 1973 (1-[3-aminopropyl]phthalans); U.S.Pat. No. 3,801,594, patented Apr. 2, 1974 (3-amino-lower-alkylindoles);U.S. Pat. No. 3,810,985, patented May 14, 1974(4-anilino-1,3,5-triazines) and French Patent No. 1,549,342, delivreNov. 4, 1968 (4-[benzoylphenylmethyl]morpholines)], no such basiccompounds are known to be commercially available, and none are known tobe under advanced investigation by pharmacologists for possiblecommercial development. The search for an effective, non-acidicanti-inflammatory agent for commercial development has thereforecontinued.

My U.S. Pat. No. 4,069,256, which is identified above in the sectionheaded RELATED APPLICATIONS, and several foreign patent publicationscorresponding thereto, for example Belgian Patent No. 837,706, grantedJuly 20, 1976, disclose compounds having the formula I below where R₁,R₂, R₃, >C═X and N═B have each of the meanings given below with respectto the compounds of formula I except that, in the patent disclosures,the group R₈ is defined as being only lower-alkyl or cyclohexyl, and thegroup corresponding to R₉, in addition to the meanings given below withrespect to the compounds of formula I, is defined as hydrogen.

SUMMARY OF THE INVENTION

In one of its composition of matter aspects, the invention relates tocertain N-{2-, 3- and 4-[R₁ -(phenyl)-C(═X)]-phenyl-lower-alkyl} amines:

2-, 3- and 4-[R₁ -(phenyl)-C(═X)]-phenyl-CHR₃ CH₂ -N═B which are usefulas anti-inflammatory agents, certain species of which are also useful asanalgesics.

DETAILED DESCRIPTION INCLUSIVE OF THE PREFERRED EMBODIMENTS

More specifically, the invention relates to N-{3-[R₁-(phenyl)-C(═X)]phenyl-lower-alkyl} amines, which are useful asanti-inflammatory agents, having the formula: ##STR1## where R₁represents hydrogen or from one to two, the same or different,lower-alkyl, hydroxy, lower-alkoxy, trifluoromethyl,lower-alkylmercapto, lower-alkylsulfinyl, lower-alkylsulfonyl or halogenselected from fluorine, chlorine or bromine; R₂ represents hydrogen, orlower-alkoxy or hydroxy in the 4-position, or lower-alkyl in either ofthe 2-, 4-, 5- or 6-positions; R₃ represents hydrogen or lower-alkyl;the group >C═X represents >C═O, >C(R₃)OH, >C(R₃)H, >C═CH₂, C═NOH or>CHN(R₃)₂ ; and N═B represents one of the groups ##STR2## where R₄ andR₅ each represent lower-alkyl; R₆ and R₇ each represent hydrogen,lower-alkyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl,3-cyclohexylpropyl or benzyl; R₉ represents lower-alkyl, cyclohexyl,cyclohexylmethyl, 2-cyclohexylethyl, 3-cycylhexylpropyl or benzyl; Zrepresents O, S or N-R₈ ; R₈ represents lower-alkyl, cycloalkyl containifrom three to seven ring carbon atoms, phenyl or phenyl-lower-alkyl; ann represents one of the integers 1, 2 and 3.

Preferred compounds of formula I are those where R₁ represents hydrogenor from one to two, the same or different, lower-alkyl, lower-alkoxy orhalogen; R₂ represents hydrogen, or lower-alkoxy or hydroxy in the4-position; and N═B represents one of the groups ##STR3## in which R₆represents hydrogen, lower-alkyl, cyclohexyl, cyclohexylmethyl,2-cyclohexylethyl or 3-cyclohexylpropyl; R₇ represents hydrogen; R₉represents cyclohexylmethyl; Z represents O or N-R₈ ; R₈ representscycloalkyl containing from three to seven ring carbon atoms, phenyl orphenyl-lower-alkyl; and R₃ and n have the meanings given above.

Particularly preferred compounds of formula I within the ambit of thepreferred aspects of the invention as described above are those where R₁represents hydrogen or from one to two, the same or different,lower-alkoxy, lower-alkyl or halogen; R₂ represents hydrogen orlower-alkoxy or hydroxy in the 4-position; >C═X represents >C═O,>C(R₃)OH, >C(R₃)H, >C═CH₂, >C═NOH or >CHNH₂ ; and N═B represents one ofthe groups. ##STR4## in which n represents the integers 1 or 2; and R₃,R₆ and R₉ have the meanings given above.

Other particularly preferred compounds within the ambit of Formula I arethose having the formula ##STR5## where R₃ is lower-alkyl

Still other particularly preferred compounds within the ambit of formulaI are those having the formula ##STR6## where >C═X is >C═O, >C═NOH or>CHN(R₃)₂ ; and R₃, all occurrences, and R₆ are each hydrogen orlower-alkyl.

Still other particularly preferred compounds within the ambit of formulaI are those having the formula ##STR7## where R₃ is hydrogen orlower-alkyl; and R₈ is cycloalkyl containing from three to seven ringcarbon atoms, phenyl or phenyl-lower-alkyl.

Also within the purview of the present invention are compounds havingthe formula: ##STR8## where the group >C═X represents >C═O and R₃represents lower-alkyl or where the group >C═X represents >CHNH₂ and R₃represents hydrogen.

Also within the purview of the present invention are compounds havingthe formula: ##STR9## where R₁ ; R₂ ; R₃ ; and C═X have the meaningsgiven above; the R₁ -(Phenyl)-(C═X)- group can be attached to either the2-, 3- or 4-position of the benzene ring of the R₂ -(Phenyl)-CR₃ R₃ 'CH₂-N═B moiety; the R₂ substituent can be attached to any position of thebenzene ring of the latter group which is not occupied by the R₁-(Phenyl)-C(═X)- group, i.e. the 2-, 3-, 4-, 5- or 6-position; R₃ 'represents hydrogen or lower-alkyl; and N═B, in addition to the meaningsgiven above, also represents one of the groups ##STR10## where R₈ ishydrogen and Y and Y' each represents O or S.

Preferred compounds of formula Ib are those where R₁, R₂ and R₈ are eachhydrogen; R₃ is lower-alkyl; R₃ ' is hydrogen or lower-alkyl; >C═Xis >C═O; the R₁ -(Phenyl)-(C═X)- group is attached to either the 3- or4-position of the benzene ring of the R₂ -(Phenyl)-CR₃ R₃ 'CH₂ -N═Bmoiety; and N═B represents one of the groups ##STR11## where Y and Y'are each O or S; and Z is O, S or N-R₈, where R₈ is hydrogen.

As used herein, the terms lower-alkyl and lower-alkoxy mean saturated,monovalent, aliphatic radicals, including branched chain radicals, offrom one to four carbon atoms, for example methyl, ethyl, propyl,isopropyl, butyl, sec.-butyl, isobutyl, methoxy, ethoxy, propoxy,isopropoxy, butoxy, sec.-butoxy and isobutoxy.

The compounds of formulas I or Ib in which the group C═X represents>C(R₃)OH where R₃ is hydrogen are prepared by reaction of an appropriate2-, 3- or 4-[R₁ -(phenyl)-CO]-phenyl-lower-alkanoyl halide of formulaIII (prepared by reaction of the corresponding acid of formula II with athionyl halide) with an appropriate amine of formula IV, H-N═B, andreduction of the resulting 2-, 3- or 4-[R₁-(phenyl)-CO]-phenyl-lower-alkanoylamine of formula V with a reagenteffective to reduce amides to amines, for example an alkali metalaluminum hydride, a trialkylaluminum or a dialkylaluminum hydride. Themethod is represented by the following reaction sequence: ##STR12##where R₁, R₂, R₃ and R₃ ' have the meanings given above, Hal representshalogen, and N═B in addition to the meanings given above also representsthe group --NHCHR₃ (CH₂)_(n) N(R₄)₂ where R₃, R₄ and n have the meaningsgiven above. The preparation of the acid halide is carried out eitherwith or without a solvent by heating the acid with a molar excess of thethionyl halide. Conversion of the halide to the amide of formula V iseffected by reacting the halide with the amine in the presence of anacid-acceptor, for example an alkali metal carbonate or bicarbonate, atri-lower-alkylamine or an excess of the amine, H-N═B. The reaction ispreferably carried out in an inert organic solvent, for examplemethylene dichloride, benzene, toluene or xylene. Reduction of the amidewith an alkali metal aluminum hydride is carried out in an inert organicsolvent, for example diethyl ether, tetrahydrofuran, dioxane or dibutylether.

The compounds corresponding to formula V having the formula ##STR13##where the group >C═X represents >CH₂, and R₁ R₂, R₃, R₃ ' and N═B havethe meanings given above, are also within the purview of the invention.The latter compounds are prepared from the corresponding compoundswhere >C═X represents >C═O by catalytic reduction of the latter over apalladium-on-charcoal catalyst at a hydrogen pressure around 50-60p.s.i.

Preferred compounds within the ambit of formula V and Va are those whereR₁ and R₂ each represent hydrogen; R₃ ' represents hydrogen; N═Brepresents one of the groups ##STR14## where R₆ represents lower-alkylor cyclohexylmethyl; R₉ represents cyclohexylmethyl; Z represents O orN-R₈ ; R₈ represents cycloalkyl containing from three to seven ringcarbon atoms, phenyl or phenyl-lower-alkyl; n represents the integer 2;and R₃ and R₄ have the meanings given above.

Particularly preferred compounds of formulas V and Va within the ambitof the preferred species described above are those having the formulas##STR15## where >C═X is >C═O or >CH₂. As indicated by the abovereaction, reduction of the 2-, 3- and 4-[R₁-(phenyl)-CO]-phenyl-lower-alkanoylamines of formula V also effectsreduction of the carbonyl group of the R₁ -(phenyl)-CO moiety to thecarbinol group, CHOH. This reduction can be avoided if desired byprotecting the carbonyl group of the R₁ -(phenyl)-CO moiety with a ketalgroup, for example the ethylene glycol ketal. The ketals are prepared byreaction of the carbonyl compound with an alcohol in the presence of anacid catalyst under dehydrating conditions. The ketal group can then beremoved by hydrolysis at a later stage after reduction of the amidefunction.

Alternatively, when the carbonyl group is reduced to the carbinol group,the carbinols can be reoxidized to the ketones if compounds where >C═Xis a carbonyl group are desired. Preferred oxidizing agents for thispurpose are chromic acid or nitric acid/perchloric acid, and it ispreferred to carry out the reaction in an inert organic solvent, forexample benzene when chromic acid is the oxidant and 1,2-dimethoxyethanewhen nitric acid/perchloric acid is the oxidant.

Another method for preparing the compounds of formulas I and Ib,where >C═X is a carbonyl group and R₂ is hydroxy or lower-alkoxy in the4-position, comprises acylating a phenyl-lower-alkylamine of formula VIwith a benzoic acid halide of formula VII, R₁ -(phenyl)-CO-Hal, underFriedel-Crafts conditions as represented by the reaction: ##STR16##where R₁, R₂, R₃ ', N═B and Hal have the meanings given above. Thereaction is carried out by adding the amine of formula VI to a stirredmixture of the acid chloride and a suitable Lewis acid which serves as aFriedel-Crafts catalyst, for example an aluminum halide or ferricchloride. A preferred catalyst is an aluminum halide.

The compounds of formulas I and Ib where the group >C═X represents acarbonyl group can also be prepared by reaction of a3-benzoylphenyl-lower-alkyl p-toluenesulfonate having the formula VIIIwith an amine, H-N═B, in the presence of an acid-acceptor according tothe reaction: ##STR17## where R₁, R₂, R₃, R₃ ' and N═B have the meaningsgiven above, and Ts represents the p-toluenesulfonyl group. The reactionis preferably carried out by heating the reactants in an inert organicsolvent, for example dimethylformamide (DMF) or a lower-alkanol.Suitable acid-acceptors are alkali metal carbonates or bicarbonates oran excess of the amine, H-N═B.

The tosylates of formula VIII are in turn prepared by a sequence ofreactions involving reduction, with an alkali metal borohydride, of a2-, 3- or 4-bromophenyl-lower-alkanaldehyde to the corresponding 2-, 3-or 4-bromophenyl-lower-alkanol; reaction of the latter with dihydropyranin the absence of solvent and in the presence of a few drops ofconcentrated hydrochloric acid to prepare the corresponding 2-, 3- or4-bromophenyl-lower-alkane tetrahydropyranyl ether; reaction of thelatter with butyl lithium followed by an appropriate R₁-(phenyl)-nitrile and hydrolysis of the tetrahydropyranyl ether group;and reaction of the resulting 2-, 3- or 4-benzoylphenyl-lower-alkanolwith p-toluenesulfonyl chloride in the presence of pyridine. The methodis represented by the following reaction sequence: ##STR18## where R₁,R₂, R₃ and R₃ ' have the meanings given above, and Ts represents thep-toluenesulfonyl group.

The compounds of formulas I and Ib where the group >C═X represents >C═Oor >C(R₃)OH where R₃ is hydrogen or lower-alkyl are prepared by reactinga 3- or 4-halophenyl-lower-alkylamine of formula IX with a lower-alkyllithium in an aprotic organic solvent, for example diethyl ether, andreacting the resulting aryl lithium directly either with a R₁-(phenyl)-carbonitrile, R₁ -(phenyl)-CN (to prepare the compoundswhere >C═X is >C═O), or with a R₁ -(phenyl)-carboxaldehyde, R₁-(phenyl)-CHO (to prepare the compounds where R₃ is hydrogen), or with aR₁ -(phenyl) lower-alkyl ketone, R₁ -(phenyl)-COR₃ (to prepare thecompounds where R₃ is lower-alkyl). During the course of the reaction ofthe aryl lithium with an aldehyde, and for reasons not completelyunderstood, some of the carbinol product (C═X is CHOH) is oxidized tothe ketone, and in such cases it is necessary to reduce the crudeproduct with an alkali metal borohydride as described hereinbelow.

The 2-, 3- and 4-halophenyl-lower-alkylamines of formula IX are in turnprepared by one of two methods depending upon the identity of the groupN═B in the final product. The compounds of formula IX where N═B is asecondary amino group are prepared by reaction of the correspondingprimary amine with a 3- or 4-halophenyl-lower-alkanal of formula X,followed by reduction of the resulting Schiff base with an alkali metalborohydride. The compounds of formula IX where N═B is a tertiary aminogroup are prepared by reaction of a 2-, 3- or 4-halophenyl-lower-alkanalof formula X with a secondary amine, conversion of the resulting 2-,3-or 4-halophenylvinylamine of formula XI to the iminium salt having theformula XII by reaction of the former with mineral acid, and reductionof the iminium salt with an alkali metal borohydride. The condensationof the aldehyde with the amine in the latter procedure is preferablycarried out in a water immiscible solvent, for example benzene, tolueneor xylene, at the reflux temperature thereof under a water separatorwhich is used to collect the water as it is produced in the reaction.The reduction of the iminium salt with an alkali metal borohydride iscarried out in an inert organic solvent, for example a lower-alkanol ordimethylformamide (DMF). The overall method is represented by thereaction sequence: ##STR19## where R₁, R₂, R₃, R₃ ', N═B and Hal havethe meanings given above, and X.sup.⊖ represents an anion of a mineralacid.

The methods described above are used to prepare the compounds offormulas I or Ib where >C═X is either a carbonyl group, >C═O, or acarbinol group, >C(R₃)OH, where R₃ is either hydrogen or lower-alkyl.The compounds of formulas I or Ib where the group >C═X has the othermeanings given are prepared by simple chemical transformations involvingthe carbonyl or carbinol groups. Thus the compounds where the group >C═Xrepresents >C(R₃)H, where R₃ is either hydrogen or lower-alkyl, areprepared by catalytic reduction with hydrogen of the correspondingcarbinol, >C(R₃)OH, in the presence of perchloric acid. A preferredcatalyst is palladium-on-charcoal, and it is preferred to carry out thereaction in glacial acetic acid as solvent. Reduction is carried out ata pressure in the range from 40-100 p.s.i.

The compounds of formulas I or Ib where >C═X is the group >C═CH₂ areprepared by dehydration of the methyl carbinols, where >C═X is the group##STR20## with concentrated sulfuric acid. The reaction is carried outby refluxing a solution of the carbinol and sulfuric acid in alower-alkanol solvent.

The compounds of formulas I or Ib where >C═X is the group >C═NOH areprepared from the corresponding ketones (>C═X is >C═O) by heating thelatter with hydroxylamine in an inert organic solvent, for example alower-alkanol.

The compounds of formulas I or Ib where >C═X is the group CHNH₂ areprepared by reducing the corresponding oximes (>C═X is >C═NOH) withsodium in a lower-alkanol. The compounds of formulas I or Ib where >C═Xis >C═NOH, apart from their usefulness as pharmaceutically activecompounds as described below, are thus also useful as intermediates forpreparation of the compounds where >C═X is >CHNH₂.

The compounds of formulas I or Ib in which >C═X represents >CHN(CH₃)₂are prepared from the corresponding primary amines by treatment of thelatter with formaldehyde in the presence of formic acid.

The compounds of formula Ia where >C═X represents >C═O are prepared byreaction of a 3-(phenyl-CO)-phenyl-CHR₃ halide of formula XIII withmorpholine according to the reaction: ##STR21## where R₃ and Hal havethe meanings given above. The reaction is carried out by reacting asolution of the halide with a molar excess of morpholine at ambienttemperature in an inert organic solvent, for example methanol, ethanol,isopropanol or DMF. A preferred solvent is DMF.

The compounds of formula Ia where the group >C═X represents >CHNH₂ areprepared from the corresponding compounds where >C═X represents >C═O byconversion of the latter to the oxime and reduction of the latter to theamine as described above.

The 2-, 3- and 4-[R₁ -(phenyl)-C═X]-phenyl-CR₃ R₃ 'CO-N═B compounds offormula V where C═X is C(R₃)H, where R₃ is hydrogen, are prepared bycatalytic reduction of the corresponding compounds of formula V whereC═X is C═O with hydrogen over a palladium-on-charcoal catalyst whichcatalyzes reduction of the ketone carbonyl group without reduction ofthe amide carbonyl group. The reduction is carried out at a pressure inthe range from 35-90 p.s.i. and at a temperature from 20°-60° C. and inan inert organic solvent, for example a lower-alkanol such as methanol,ethanol or isopropanol.

The amines of formula IV where --N═B is the group: ##STR22## where R₈ ishydrogen, lower-alkyl, cycloalkyl, phenyl or phenyl-lower-alkyl areknown compounds.

The amines in which --N═B is the group: ##STR23## where n is 2 are alsoknown, having been generally described in U.S. Pat. No. 3,238,215. Asdescribed therein, they are prepared by catalytic reduction overplatinum oxide of appropriate R₃, R₆ or R₇ -substituted pyridines, whichare commercially available.

The amines where N═B is the group: ##STR24## where n is the integer 1and R₇ is hydrogen are prepared by refluxing a mixture of an appropriatealkanedione, ammonium acetate and glacial acetic acid, and catalyticreduction over platinum oxide of the resulting 2-R₃ -5-R₆ -pyrroleaccording to the reaction sequence: ##STR25## where R₃ and R₆ have themeanings given above.

Alternatively, the amines in which --N═B is the group: ##STR26## where nis 1 and R₇ is hydrogen are prepared by reaction of a Grignard reagent,R₆ MgHal, with a 4-R₃ -4-halobutyronitrile, R₃ -CH-(Hal)-(CH₂)₂ -CN;direct cyclization of the resulting 1-amino-1-R₆ -4-R₃ -4-halobutene;and catalytic reduction of the resulting 2-R₆ -5-R₃ -4,5-dihydropyrroleas indicated by the reaction sequence: ##STR27## where R₃, R₆ and Halhave the meanings given above.

The amines where --N═B is the group: ##STR28## are advantageouslyprepared, like the amines where --N═B is the group: ##STR29## where n is2, by catalytic reduction over platinum oxide of the corresponding 4-R₉-pyridine.

The amines where --N═B is the group: ##STR30## where R₃ and R₇ arehydrogen, n is the integer 3, and R₆ has the meanings given above areprepared by Beckmann rearrangement of an appropriate R₆-substituted-cyclohexanone oxime and reduction, with lithium aluminumhydride, of the resulting lactam according to the reaction: ##STR31##

The amines of formula VI where --N═B is the group: ##STR32## where Z isO are prepared according to the method described in British Patent No.835,717 which comprises passing a vaporized mixture of a glycol etherhaving the formula ##STR33## together with ammonia and hydrogen over ahydrogenation/dehydrogenation catalyst based on either nickel or cobaltat a temperature from 150° to 250° C. A preferred catalyst is nickel onkieselguhr.

The amines of formula IV in which --N═B is the group: ##STR34## where Zis S are preferably prepared by the methods described by Idson et al.,J. Am. Chem. Soc. 76, 2902 (1954) which involves either the reaction ofsodium sulfide with an appropriate bis-2-haloethylamine: ##STR35## orthe reaction of ammonia with an appropriate bis-2-haloethyl sulfide:##STR36## where R₃ and R₆ have the meanings given above, and Halrepresents halogen.

The amines of formula IV in which N═B is the group: ##STR37## where Yand Y' represent O or S are prepared by reaction of commerciallyavailable 4,4-dihydroxypiperidine with either ethylene glycol,2-mercaptoethanol or 1,2-ethanedithiol (to prepare the respectivecompounds where Y and Y' are both O, or Y is O and Y' is S, or Y and Y'are both S). The reaction is carried out by refluxing a solution of thereactants in the presence of a catalytic amount of a non-volatile strongacid, for example p-toluenesulfonic acid, in a water immiscible organicsolvent, for example benzene, toluene or xylene, under a Dean-Stark trapuntil no further water is produced in the reaction and collected in thetrap.

The 2-, 3- and R₄ -[R₁ -(phenyl)-CO]-phenyl-lower-alkanoic acids offormula II where R₂ is hydrogen or lower-alkyl are generally knowncompounds prepared by the methods described in British Patent No.1,164,585. Although the compounds of formula II where R₂ is hydroxy canalso be prepared by the methods used to prepare the compounds where R₂is hydrogen or lower-alkyl and the compounds of formula II so-preparedconverted, as described above, to the final products of formulas I orIb, it is preferred to prepare the compounds of formulas I or Ib whereR₂ is hydroxy from a 4-lower-alkoxy-phenyl-lower-alkanoic acid byconversion of the latter to the corresponding acid halide; conversion ofthe latter to the corresponding4-lower-alkoxyphenyl-lower-alkanoyl-amine by reaction of the acid halidewith an amine, H-N═B, and reduction of the resulting amide with areagent effective to reduce amides to amines, for example an alkalimetal aluminum hydride; reaction of the resulting amine with an acidhalide, R₁ -(phenyl)-CO-Hal, using Friedel-Crafts conditions; andfinally cleavage of the lower-alkoxy group to the hydroxy group, usingwell-known methods such as heating with hydrobromic acid. The method forthe preparation of the N-{3-[R₁ -(phenyl)-CO]-phenyl-lower-alkyl}amineis represented by the following reaction sequence: ##STR38## where R₁,R₃, R₃ ', R₄, N═B and Hal have the meanings given above. The reactionconditions for the first four reactions in this reaction sequence havebeen described above, and cleavage of the ether with hydrobromic acid isa conventional reaction well known to the organic chemist.

The 2-, 3- and 4-halophenyl-lower-alkanals of formula X where R₃ ' ishydrogen are prepared via the Darzens glycidic ester condensation byreaction of a 2-, 3- or 4-halo-lower-alkanophenone with a lower-alkylhaloacetate in the presence of an alkali metal alkoxide andsaponification and decarboxylation of the resulting glycidic ester. Themethod is represented by the following reaction sequence: ##STR39##

The novel compounds of the instant invention are the compounds offormulas I, Ia and V and the acid-addition salts of the componds offormulas I, Ia, Ib and V which contain a basic amine group capable ofsalt formation with acids, i.e. the compounds of formula V where N═B isthe group ##STR40## where Z is N-R₈. The compounds of formulas I, Ia, Iband V in free base form are converted to the acid-addition salt form byinteraction of the base with an acid. In like manner, the free base canbe regenerated from the acid-addition salt form in the conventionalmanner, that is by treating the salts with cold, weak aqueous bases, forexample alkali metal carbonates and alkali metal bicarbonates. The basesthus regenerated can then be interacted with the same or a differentacid to give back the same or a different acid-addition salt. Thus thenovel bases and all of their acid-addition salts are readilyinterconvertible.

It will thus be appreciated that formulas I, Ia, Ib and V not onlyrepresent the structural configuration of the bases of formulas I, Ia,Ib and V but are also representative of the structural entities whichare common to all of the compounds of formulas I, Ia, Ib and V, whetherin the form of the free base or in the form of the acid-addition saltsof the base. It has been found that by virtue of these common structuralentities, the bases and their acid-addition salts have inherentpharmacological activity of a type to be more fully describedhereinbelow. This inherent pharmacological activity can be enjoyed inuseful form for pharmaceutical purposes by employing the free basesthemselves or the acid-addition salts formed frompharmaceutically-acceptable acids, that is acids whose anions areinnocuous to the animal organism in effective doses of the salts so thatbeneficial properties inherent in the common structural entityrepresented by the free bases is not vitiated by side effects ascribableto the anions.

In utilizing this pharmacological activity of the salts of theinvention, it is preferred, of course, to use pharmaceuticallyacceptable salts. Although water-insolubility, high toxicity, or lack ofcrystalline character may make some particular salt species unsuitableor less desirable for use as such in a given pharmaceutical application,the water-insoluble or toxic salts can be converted to the correspondingpharmaceutically-acceptable bases by decomposition of the salt withaqueous base as explained above, or alternatively they can be convertedto any desired pharmaceutically-acceptable acid-addition salt by doubledecomposition reactions involving the anion, for example by ion-exchangeprocedures.

Moreover, apart from their usefulness in pharmaceutical applications,the salts are useful as characterizing or identifying derivatives of thefree bases or in isolation or purification procedures. Like all of theacid-addition salts, such characterizing or purification saltderivatives can, if desired, be used to regenerate thepharmaceutically-acceptable free bases by reaction of the salts withaqueous base, or alternatively can be converted to apharmaceutically-acceptable acid-addition salt by, for example,ion-exchange procedures.

It will be appreciated from the foregoing that all of the acid-additionsalts of the new bases are useful and valuable compounds, regardless ofconsiderations of solubility, toxicity, physical form and the like, andare accordingly within the purview of the instant invention.

The novel feature of the compounds of the invention, then, resides inthe concept of the bases and cationic forms of the new N-{2-, 3- and4-[R₁ -(phenyl)-C(═X)]-phenyl-lower-alkyl}amines and not in anyparticular acid moiety or acid anion associated with the salt forms ofthe compounds; rather, the acid moieties or anions which can beassociated with the salt forms are in themselves neither novel norcritical and therefore can be any acid anion or acid-like substancecapable of salt formation with the bases. In fact, in aqueous solutions,the base form or water-soluble acid-addition salt form of the compoundsof the invention both possess a common protonated cation or ammoniumion.

Thus appropriate acid-addition salts are those derived from such diverseacids as formic acid, acetic acid, isobutyric acid,alpha-mercaptopropionic acid, malic acid, fumaric acid, succinic acid,succinamic acid, tartaric acid, citric acid, lactic acid, benzoic acid,4-methoxybenzoic acid, phthalic acid, anthranilic acid,1-naphthalenecarboxylic acid, cinnamic acid, cyclohexanecarboxylic acid,mandelic acid, tropic acid, crotonic acid, acetylenedicarboxylic acid,sorbic acid, 2-furancarboxylic acid, cholic acid, pyrenecarboxylic acid,2-pyridinecarboxylic acid, 3-indoleacetic acid, quinic acid, sulfamicacid, methanesulfonic acid, isethionic acid, benzenesulfonic acid,p-toluenesulfonic acid, benzenesulfinic acid, butylarsonic acid,diethylphosphonic acid, p-aminophenylarsinic acid, phenylstibnic acid,phenylphosphinous acid, methylphosphinic acid, phenylphosphinic acid,hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid,perchloric acid, nitric acid, sulfuric acid, phosphoric acid,hydrocyanic acid, phosphotungstic acid, molybdic acid, phosphomolybdicacid, pyrophosphoric acid, arsenic acid, picric acid, picrolonic acid,barbituric acid, boron trifluoride, and the like.

The acid-addition salts are prepared by reacting the free base and theacid in an organic solvent and isolating the salt directly or byconcentration of the solution.

Due to the presence of at least one and as many as four asymmetriccenters in the compounds of the invention, i.e. the carbon atom adjacentthe phenyl ring to which the R₃ and R₃ ' groups are attached and thevarious asymmetric centers in the group --N═B to which the groups R₃,R₄, R₅, R₆, R₇ and R₉ are attached, the compounds of the invention canexist in stereochemically isomeric forms which are all considered to bewithin the purview of the invention. If desired, the isolation or theproduction of a particular stereochemical form can be accomplished byapplication of general principles known in the art.

In standard pharmacological test procedures, the compounds of formulasI, Ia, Ib, V and Va have been found to possess anti-inflammatoryactivity and are useful as anti-inflammatory agents. Certain species offormulas I and Ib have also been found to possess analgesic activity andare thus useful as analgesic agents. Moreover, certain compounds offormula I have also been found to have anti-viral activity and are thusalso useful as anti-viral agents.

Anti-inflammatory activity was determined using (1) the inhibition ofcarrageenin-induced foot edema test essentially described by Winter etal., Proc. Soc. Exp. Biol. and Med. 111, 554 (1962) as modified by VanArman et al., J. Pharmacol. Exptl. Therap. 150, 328 (1965) and (2) amodification of the inhibition of adjuvant-induced arthritis testdescribed by Pierson, J. Chronic Diseases 16, 863 (1963) and Glenn etal., Am. J. Vet. Res. 26, 1180 (1965).

The test procedures used to determine the analgesic activities of thecompounds have been described in detail in the prior art and are asfollows: the acetylcholine-induced abdominal constriction test, which isa primary analgesic screening test designed to measure the ability of atest agent to suppress acetylcholine-induced abdominal constriction inmice, described by Collier et al., Brit. J. Pharmacol. Chemotherap. 32,295 (1968); a modification of the anti-bradykinin test, which is also aprimary analgesic screening procedure, described by Berkowitz et al., J.Pharmacol. Exp. Therap. 177, 500-508 (1971), Blane et al., J. Pharm.Pharmacol. 19, 367-373 (1967), Botha et al., Eur. J. Pharmacol. 6,312-321 (1969) and Deffenu et al., J. Pharm. Pharmacol. 18, 135 (1966);the phenyl-p-quinone-induced writhing test, also a primary analgesicscreening test, designed to measure the ability of a test agent toprevent phenyl-p-quinone-induced writhing in mice, described by Pearland Harris, J. Pharmacol. Exptl. Therap. 154, 319-323 (1966); the rattail flick radiant thermal heat analgesic (agonist) test described byD'Amour and Smith, J. Pharmacol. Exptl. Therap. 72, 74 (1941) asmodified by Bass and VanderBrook, J. Am. Pharm. Assoc. Sci. Ed. 41, 569(1956); and the phenazocine antagonist test, which is designed tomeasure the ability of a test agent to antagonize the effect ofphenazocine in the above-indicated rat tail flick response test,described by Harris and Pierson, J. Pharmacol. Exptl. Therap. 143, 141(1964).

The in vitro anti-viral activity of the compounds against herpes simplexviruses types 1 and 2 was demonstrated by the addition of the compoundsto tissue cultures infected with herpes virus. Monolayers of tissuecultures (BSC, cell line, monkey kidney) were infected with one hundredTCID₅₀ (Tissue Culture Infectious Dose₅₀) of infectious virus. After onehour of virus adsorption, fresh maintenance medium containing variousconcentrations of the test compounds was added to the monolayers.Cultures were then incubated at 36°-37° C., and after forty-eight andseventy-two hours, cultures were examined microscopically. In theinfected control tubes as well as in those containing inactivecompounds, viral growth is indicated by the production of characteristiccytopathic effects with the destruction of the cells. In the presence ofan active compound, cells grow normally similar to those in the tissueculture control. Simultaneously with the anti-viral evaluation, thetoxicity of each compound was evaluated in separate cultures. Identicalconcentrations of the test compound were added to the tissue culturemonolayers in the absence of virus. Those concentrations of the compoundwhich show toxic effects on the cells were not considered in theanti-viral evaluation. The activity of the compounds was expressed interms of the Minimal Inhibitory Concentration (MIC), where the MIC isdescribed as the lowest concentration of the test compound whichcompletely inhibits the growth of the virus.

The compounds of the invention can be prepared for use by incorporatingthem in unit dosage form as tablets or capsules for oral administrationeither alone or in combination with suitable adjuvants such as calciumcarbonate, starch, lactose, talc, magnesium stearate, gum acacia, andthe like. Still further, the compounds can be formulated for oraladministration in aqueous alcohol, glycol or oil solutions or oil-wateremulsions in the same manner as conventional medicinal substances areprepared.

The molecular structures of the compounds of the invention were assignedon the basis of study of their infrared, ultraviolet, and NMR spectra,and confirmed by the correspondence between calculated and found valuesfor elementary analyses for the elements.

The following examples will further illustrate the invention without,however, limiting is thereto. All melting points are uncorrected.

Preparation of Amine Intermediates Preparation I

In three separate runs, 33.8 g. (0.20 mole) portions of2-benzylpyridine, each in a solution of about 225 ml. of ethanol and 22ml. of concentrated hydrochloric acid, were reduced over 4.0 g. portionsof platinum oxide catalyst under about 54 p.s.i. of hydrogen at atemperature of about 55°-61° C. When reduction was complete in eachcase, the catalyst was removed by filtration, washed with small portionsof ethanol, and the combined filtrates evaporated to a volume of about80 ml. and diluted to approximately 500 ml. with boiling acetone. Thesolid which precipitated was collected, washed with acetone and driedgiving a combined yield of 124.8 g. of 2-cyclohexylmethylpiperidinehydrochloride, m.p. 211°-213° C. The free base was regenerated from thehydrochloride by neutralization of an aqueous solution of the latterwith potassium carbonate, extraction of the oily base into benzene,evaporation of the benzene solution to dryness, and distillation of theresidual oil in vacuo at 55°-59° C./0.27 mm. There was thus obtained89.4 g. of 2-cyclohexylmethylpiperidine.

Preparation 2

A mixture of 15.52 g. (0.10 mole) of 2-phenylpyridine, 15 ml. ofconcentrated hydrochloric acid and 2.0 g. of platinum oxide in 185 ml.of ethanol in a pressure bottle was heated and shaken in a Parrhydrogenator under 55 p.s.i. of hydrogen at a temperature around 60° C.When reduction was complete in about eight hours, the catalyst wasremoved by filtration and the filtrate concentrated to about 50 ml. anddiluted with 200 ml. of acetone. The solid which separated was collectedand dried to give 14.54 g. of 2-cyclohexylpiperidine hydrochloride, m.p.251°-253° C.

Preparation 3

A mixture of 9.1 g. (0.05 mole) of 2-stilbazole (Shaw et al., J. Chem.Soc. 1933, 77-79) and 1.0 g. of platinum oxide in a solution of 240 ml.of ethanol and 10 ml. of concentrated hydrochloric acid in a pressurebottle was heated and shaken on a Parr hydrogenator under about 55p.s.i. of hydrogen at a temperature of about 60° C. When reduction wascomplete in about eight hours, the catalyst was removed by filtration,the filtrate concentrated to a volume of about 50 ml. and diluted withabout 200 ml. of acetone. The solid which separated was collected anddried to give 9.6 g. of 2-(2-cyclohexylethyl)piperidine hydrochloride,m.p. 155°-156° C.

Preparation 4

A solution of 78.1 g. (0.84 mole) of 4-methylpyridine and 89.0 g. (0.84mole) of benzaldehyde in 103 g. of acetic anhydride was heated withstirring under reflux for twenty-four hours. The mixture was thenconcentrated to a thick oil in vacuo and the residue dissolved in hotethanol. The solid which separated was collected and recrystallized fromethanol to give 57.9 g. of 4-styrylpyridine, m.p. 131.5°-133° C.

The latter (36.2 g., 0.2 mole), dissolved in 220 ml. of absolute ethanoland 30 ml. of concentrated hydrochloric acid, was reduced over 3.0 g. ofplatinum oxide under a hydrogen pressure of about 55 p.s.i. The productwas worked up in the manner described above in Preparation 1 andisolated in the form of the hydrochloride salt to give 43.5 g. of4-(2-cyclohexylethyl)piperidine hydrochloride, m.p. 246°-248° C.

Preparation 5

4-Phenylpyridine (15.5 g., 0.1 mole) dissolved in 185 ml. of absoluteethanol and 15 ml. of concentrated hydrochloric acid was reduced withhydrogen over 2 g. of platinum oxide under a hydrogen pressure of about55 p.s.i. The product was worked up in the manner described above inPreparation 1 and isolated in the form of the hydrochloride salt to give15.3 g. of 4-cyclohexylpiperidine hydrochloride. (The free base givesm.p. 106°-109° C.)

Preparation 6

To a mixture of 8.6 g. (0.36 mole) of magnesium turnings in 150 ml. ofdry ether was added in small portions with cooling and stirring asolution of 45.0 g. (0.36 mole) of benzyl chloride in 75 ml. ofanhydrous ether. When addition was complete, the mixture was stirred forabout one hour and then treated dropwise with a solution of 26.6 g. of4-chlorobutyronitrile in 95 ml. of ether. When addition was complete,the ether was gradually distilled off while replacing with an equalvolume of toluene. The mixture was heated under reflux (at about 109°C.) for about thirty minutes, cooled to about 15° C., treated dropwisewith 300 ml. of 10% aqueous ammonium chloride, filtered and the organiclayer separated. The latter was washed with three 100 ml. portions ofdilute hydrochloric acid, and the combined acid extracts were basifiedwith solid potassium carbonate. Extraction of the mixture with ether andremoval of the solvent from the combined organic extracts afforded anoil which was distilled in vacuo to give 13.05 g. of2-benzyl-4,5-dihydropyrrole, b.p. 123°-125° C./13 mm., n_(D) ²⁵ 1.5405.

The latter, dissolved in 210 ml. of ethanol and 15 ml. of concentratedhydrochloric acid was reduced with hydrogen over 2 g. of platinum oxideunder a hydrogen pressure of about 50 p.s.i. The mixture was worked upin the manner described above in Preparation 1 and the product isolatedin the form of the hydrochloride salt to give 16.8 g. of2-cyclohexylmethylpyrrolidine hydrochloride, m.p. 130.5-131.5° C. (fromacetone).

Preparation 7

To a suspension of 11.2 g. (1.6 mole) of lithium wire in 600 ml. ofanhydrous ether was added dropwise 125.6 g. (0.8 mole) of bromobenzene.When addition was complete, the mixture was stirred for about a halfhour and then treated dropwise first with a solution of 74.4 g. (0.8mole) of picoline in 100 ml. of anhydrous ether and then, after stirringfor fifteen minutes, with a solution of 74.0 g. (0.4 mole) of2-phenylethyl bromide in 100 ml. of ether. The mixture was stirred atambient temperature for about twelve hours and then poured with stirringonto 300 g. of ice. When all excess lithium had reacted, the layers wereseparated, the aqueous layer washed with additional ether, and thecombined organic portions were washed with brine, dried and taken todryness to give a residual oil which was distilled in vacuo to give 41.3g. of 2-(3-phenylpropyl)pyridine, b.p. 76°-78° C./0.05 mm., n_(D) ²⁵1.5592.

The latter (19.7 g., 0.1 mole) dissolved in 235 ml. of ethanol and 15ml. of concentrated hydrochloric acid was reduced with hydrogen over 2g. of platinum oxide under a hydrogen pressure of around 55 p.s.i. atabout 65° C. The product was worked up in the manner described above inPreparation 1 and isolated in the form of the hydrochloride salt to give22.2 g. of 2-(3-cyclohexylpropyl)piperidine hydrochloride, m.p.175°-176.5° C. (from ethyl acetate).

Preparation 8

Catalytic reduction of 3-benzylpyridine in glacial acetic acid over aplatinum oxide catalyst and isolation of the product using the proceduredescribed above in Preparation 1 affords 3-benzylpiperidine.

Preparation of Final Products EXAMPLE 1

A solution of 25.4 g. (0.1 mole) of α-(3-benzoylphenyl)propionic acid in40 ml. of benzene was added to 19.8 g. (0.166 mole) of thionyl chlorideand the solution refluxed for two and a half hours. The solvent was thenremoved in vacuo, and the resulting oil (28 g.) consisting ofα-(3-benzoylphenyl)propionyl chloride was dissolved in 40 ml. of diethylether and added with stirring over a thirty minute period to a solutionof 2-cyclohexylmethylpiperidine in 80 ml. of diethyl ether. The mixturewas stirred for about forty-eight hours at ambient temperature, thenfiltered, the filter washed with ether, and the combined filtrate washedonce with dilute acid, once with brine, once with aqueous potassiumbicarbonate and evaporated to dryness to give 48.2 g. of2-cyclohexylmethyl-1-[α-(3-benzoylphenyl)propionyl]piperidine as a paleamber glass.

The latter (35.5 g., 0.085 mole) was dissolved in 200 ml. of diethylether and the solution added dropwise with stirring to a mixture of 8.08g. (0.21 mole) of lithium aluminum hydride in 200 ml. of ether whilemaintaining the temperature at 10°-15° C. The reaction mixture wasstirred at ambient temperature for three and one half hours, decomposedby the dropwise addition of 8.1 ml. of water, followed by 8.1 ml. of 15%sodium hydroxide and an additional 22.2 ml. of water. The mixture wasthen stirred for one hour, filtered, and the filtrate evaporated todryness to give 34.0 g. of an oil, 10.5 g. of which was chromatographedover 200 g. of alumina and eluted with a solution of 60% hexane/40%ether. The early fractions were removed and evaporated to dryness togive 8.0 g. of2-cyclohexylmethyl-1-{2-[3-(α-hydroxybenzyl)phenyl]propyl}piperidine asa viscous oil.

Anal. Calcd. for C₂₈ H₃₉ NO: C,82.91; H,9.69; N,3.45. Found: C,83.12;H,9.80; N,3.49.

EXAMPLES 1A-1D

Following a procedure similar to that described in Example 1, thefollowing compounds of formula I were similarly prepared:

Example 1A

2-Cyclohexylmethyl-1-{2-[3-(α-hydroxybenzyl)phenyl]ethyl}piperidine,m.p. 122°-124° C. (5.8 g. from benzene/hexane) prepared by reaction of42 g. (0.16 mole) of 3-benzoylphenylacetyl chloride (German PatentAppln. No. 2,243,444, published Mar. 8, 1944) with 31.7 g. (0.175 mole)of 2-cyclohexylmethylpiperidine in 150 ml. of ether in the presence of19.4 g. (0.192 mole) of triethylamine and reduction of the resulting2-cyclohexylmethyl-1-[(3-benzoylphenyl)acetyl]piperidine (46 g.) with 13g. (0.35 mole) of lithium aluminum hydride in 325 ml. of ether.

Anal. Calcd. for C₂₇ H₃₇ NO: C,82.81; H,9.52; N,3.58. Found: C,83.01;H,9.54; N,3.52.

Example 1B

2,6-Dimethyl-1-{2-[3-(α-hydroxybenzyl)phenyl]ethyl}piperidine, m.p.115°-117° C. (9.53 g. from benzene/hexane) prepared by reaction of 42 g.(0.16 mole) of 3-benzoylphenylacetyl chloride with 19.8 g. (0.175 mole)of 2,6-dimethylpiperidine in 150 ml. of ether in the presence of 19.4 g.(0.092 mole) of triethylamine and reduction of the resulting2,6-dimethyl-1-[(3-benzoylphenyl)acetyl]piperidine (49 g.) with 13.9 g.(0.365 mole) of lithium aluminum hydride in 300 ml. of ether.

Anal. Calcd. for C₂₂ H₂₉ NO: C,81.69; H,9.04; N,4.33. Found: C,81.83;H,9.04; N,4.32.

Example 1C

4-[2-(3-Benzoylphenyl)ethyl]morpholine hydrochloride monohydrate, m.p.177.5°-180° C. (29.0 g. from acetone) prepared by reaction of 46.5 g.(0.18 mole) of 3-benzoylphenylacetyl chloride with 17.2 g. (0.198 mole)of morpholine in 225 ml. of methylene dichloride in the presence of 21.5g. (0.211 mole) of triethylamine; conversion of the resulting 49 g. of4-[(3-benzoylphenyl)acetyl]morpholine to the corresponding ethyleneglycol ketal by reaction of the former with 125 ml. of ethylene glycolin 1250 ml. of benzene in the presence of 2.5 g. of p-toluenesulfonicacid; and reduction of the resulting ketal (58.6 g.) with 11.8 g. (0.31mole) of lithium aluminum hydride in 280 ml. of ether, followed byhydrolysis of the ketal by stirring the product at 55°-60° C. with 300ml. of 1.5 N hydrochloric acid for forty-five minutes.

Anal. Calcd. for C₁₉ H₂₁ NO₂.HCl.H₂ O: C,65.23; H,6.91; Cl,10.13. Found:C,65.38; H,6.88; Cl,10,19.

Example 1D

N-[2-(3-Benzoylphenyl)ethyl]-N-(3-dimethylaminopropyl)aminedihydrochloride hemi-hydrate, m.p. 194°-197° C. (11.1 g. of the freebase obtained as a dark oil, a small amount converted to thedihydrochloride) prepared by reaction of 46.3 g. (0.167 mole) of3-benzoylphenylacetyl chloride with 30.2 g. (0.3 mole) of3-dimethylaminopropylamine in 200 ml. of methylene dichloride in thepresence of 20.1 g. (0.2 mole) of triethylamine; conversion of theresulting 9 g. ofN-[(3-benzoylphenyl)acetyl]-N-(3-dimethylaminopropyl)amine to thecorresponding ethylene glycol ketal by reaction of 15 g. of the formerwith 37.5 ml. of ethylene glycol in the presence of 9.75 g. ofp-toluenesulfonic acid in 395 ml. of benzene; and reduction of theresulting ketal (15.6 g.) with 3.2 g. (0.084 mole) of lithium aluminumhydride in a solution of 50 ml. of dioxane and 50 ml. of di-n-butylether, followed by hydrolysis of the ketal by warming it for one hour in200 ml. of dilute hydrochloric acid at 55° C.

Anal. Calcd. for C₂₀ H₂₆ N₂ O.2HCl.1/2H₂ O: C,61.22; H,7.43; Cl,18.01.Found: C,61.97; H,7.48; Cl,17.70.

Following a procedure similar to that described in Example 1, thefollowing 3-[R₁ -(phenyl)-CO]-phenyl-lower-alkanoylamines of formula Vwere similarly prepared:

Example 1E

4-Cyclohexyl-1-[α-(3-benzoylphenyl)propionyl]piperazine hydrochloride,m.p. 208°-209° C. (10.7 g. from isopropanol/diethyl ether) prepared byreaction of 8.2 g. (0.03 mole) of α-(3-benzoylphenyl)propionyl chloridewith 4.9 g. (0.03 mole) of 1-cyclohexylpiperazine in 60 ml. of methylenedichloride in the presence of 3.6 g. (0.036 mole) of triethylamine andconversion of the crude base (11.4 g.) thus obtained to thehydrochloride salt in ethereal hydrogen chloride.

Example 1F

4-Phenyl-1-[α-(3-benzoylphenyl)propionyl]piperazine, m.p. 121°-123° C.(9.1 g. from benzene/hexane) prepared by reaction of 8.2 g. (0.03 mole)of α-(3-benzoylphenyl)propionyl chloride with 4.7 g. (0.03 mole) of1-phenylpiperazine in 70 ml. of methylene dichloride in the presence of3.6 g. (0.036 mole) of triethylamine.

Example 1G

4-Benzyl-1-[α-(3-benzoylphenyl)propionyl]piperazine hydrochloride, m.p.225°-226.5° C. (9.0 g. from ethanol) prepared by reaction of 9.0 g.(0.033 mole) of α-(3-benzoylphenyl)propionyl chloride with 5.3 g. (0.03mole) of 1-benzylpiperazine in 75 ml. of methylene dichloride in thepresence of 3.6 g. (0.036 mole) of triethylamine and conversion of thecrude base thus obtained (12.6 g.) to the hydrochloride salt.

Example 1H

4-Cyclohexyl-1-[(3-benzoylphenyl)acetyl]piperazine, m.p. 107°-109° C.(6.1 g. from hexane) prepared by reaction of 8.5 g. (0.033 mole) of(3-benzoylphenyl)acetyl chloride with 5.0 g. (0.03 mole) of1-cyclohexylpiperazine in 75 ml. of methylene dichloride in the presenceof 3.6 g. (0.036 mole) of triethylamine.

Example 1J

4-Cyclopentyl-1-[α-(3-benzoylphenyl)propionyl]piperazine hydrochloride,m.p. 178°-179° C. (10.3 g. from acetone/diethyl ether) prepared byreaction of 9.0 g. (0.033 mole) of α-(3-benzoylphenyl)propionyl chloridewith 4.6 g. (0.03 mole) of 1-cyclopentylpiperazine in 100 ml. ofmethylene dichloride in the presence of 3.6 g. (0.036 mole) oftriethylamine.

Example 1K

4-Cycloheptyl-1-[α-(3-benzoylphenyl)propionyl]piperazine hydrochloride,m.p. 201°-204° C. (10.0 g. from acetone/diethyl ether) prepared byreaction of 9.0 g. (0.033 mole) of α-(3-benzoylphenyl)propionyl chloridewith 5.5 g. (0.03 mole) of 1-cycloheptylpiperazine in 100 ml. ofmethylene dichloride in the presence of 3.6 g. (0.036 mole) oftriethylamine and conversion of the crude base thus obtained (12.5 g.)to the hydrochloride salt.

Example 1L

4-Cyclohexylmethyl-1-[α-(3-benzoylphenyl)propionyl]piperidine, a viscouspale amber glass, prepared by reaction of 6.3 g. (0.02 mole) ofα-(3-benzoylphenyl)propionyl chloride with 3.81 g. (0.02 mole) of4-cyclohexylmethylpiperidine in 75 ml. of methylene dichloride in thepresence of 2.57 g. (0.025 mole) of triethylamine.

Example 1M

4-Cycloheptyl-1-[(3-benzoylphenyl)acetyl]piperazine hydrochloride, m.p.231°-233° C. (2.77 g. from acetone) prepared by reaction of 7.0 g.(0.026 mole) of (3-benzoylphenyl)acetyl chloride with 4.1 g. (0.023mole) of 1-cycloheptylpiperazine in 55 ml. of methylene dichloride inthe presence of 2.78 g. (0.028 mole) of triethylamine.

EXAMPLE 2

Following a procedure similar to that described in Example 1,2,6-dimethyl-1-[α-(3-benzoylphenyl)propionyl]piperidine (14.3 g. as anoil) was prepared from 12.7 g. of α-(3-benzoylphenyl)propionic acid, 10g. (0.084 mole) of thionyl chloride, 6.22 g. (0.055 mole) of2,6-dimethylpiperidine and 6.05 g. (0.06 mole) of triethylamine, and theresulting amide (14.3 g.) reduced with 3.9 g. (0.103 mole) of lithiumaluminum hydride in diethyl ether to give 13.2 g. of2,6-dimethyl-1-{2-[3-(α-hydroxybenzyl)phenyl]propyl}piperidine as ayellow oil.

Anal. Calcd. for C₂₃ H₃₁ NO: C,82.34; H,8.71; N,4.18. Found: C,82,22;H,8.82; N,4.15.

EXAMPLES 2A-D

Following a procedure similar to that described in Example 1, thefollowing compounds of formula I are similarly prepared:

Example 2A

N-t-Butyl-N-{2-[3-(α-hydroxy-4-methyl-2-chlorobenzyl)phenyl]propyl}amineprepared by reaction of α-[3-(4-methyl-2-chlorobenzoyl)phenyl]propionylchloride with t-butylamine and reduction, with lithium aluminum hydride,of the resultingN-t-butyl-N-{α-[3-(4-methyl-2-chlorobenzoyl)phenyl]propionyl}-amine;

Example 2B

N-Benzyl-N-t-butul-N-{2-[3-(α-hydroxy-3-trifluoromethylbenzyl)phenyl]propyl}amineprepared by reaction of α-[3-(3-trifluoromethylbenzoyl)phenyl]propionylchloride with N-benzyl-N-t-butylamine and reduction, with lithiumaluminum hydride, of the resultingN-benzyl-N-t-butyl-N-{α-[3-(3-trifluoromethylbenzoyl)phenyl]propionyl}amine;

Example 2C

N,N-Di-isobutyl-N-{2-[3-(α-hydroxy-2,4-dichlorobenzyl)phenyl]propyl}amineprepared by reaction of α-[3-(2,4-dichlorobenzoyl)phenyl]propionylchloride with N,N-di-isobutylamine and reduction, with lithium aluminumhydride, of the resultingN,N-di-isobutyl-N-{α-[3-(2,4-dichlorobenzoyl)phenyl]propionyl}amine; and

Example 2D

4-(2-Cyclohexylethyl)-1-{2-[3-(α-hydroxy-2-bromobenzyl)-4-methylphenyl]propyl}piperidineprepared by reaction of α-[3-(2-bromobenzoyl)-4-methylphenyl]propionylchloride with 4-(2-cyclohexylethyl)piperidine and reduction, withlithium aluminum hydride, of the resulting4-(2-cyclohexylethyl)-1-{α-[3-(2-bromobenzoyl)-4-methylphenyl]propionyl}piperidine.

EXAMPLE 3

To 220 g. (1.65 moles) of aluminum chloride was added with vigorousstirring over a twenty minute period 81 g. (0.67 mole) of acetophenone.The resulting mixture was treated dropwise with stirring over a fortyminute period with 120 g. (0.8 mole) of bromine. When addition wascomplete, the mixture was stirred for an additional fifteen minutes andthen extracted with four 150 ml. portions of ether. The combined etherextracts were washed once with water, once with 10% potassiumbicarbonate, once with saturated brine, dried over anhydrous sodiumsulfate, and evaporated to dryness to give 141 g. of an oil which wasdistilled in vacuo to give 108.7 g. of 3-bromoacetophenone, b.p.71.5°-76° C./0.5 mm.

To 2,200 ml. of isopropanol in a three-necked round bottom flask flushedwith nitrogen was added in pieces 60 g. (2.6 moles) of sodium. When allthe sodium had dissolved, the mixture was cooled to about 7°-8° C. andtreated over a period of thirty minutes with a solution of 318 g. (1.6moles) of 3-bromoacetophenone and 352 g. (2.88 moles) of ethylchloroacetate. The mixture was stirred at 7°-8° C. for five hours andthen at ambient temperature for about forty-eight hours, refluxed at onehour, distilled to remove about one liter of isopropanol, and theresidue diluted with 1900 ml. of water and 1200 ml. of toluene andstirred. The layers were separated, the aqueous layer was extracted withadditional toluene, and the combined toluene extracts were washed withsaturated brine, dried, and evaporated to dryness to give 558.8 g. of abrown liquid which was combined with a solution of 70 g. of sodiumhydroxide in 225 ml. of water and 1200 ml. of absolute ethanol andrefluxed for about twelve hours. The mixture was then taken to drynessin vacuo to give 575.6 g. of a solid which was dissolved in water,acidified with dilute hydrochloric acid, and the mixture extracted withbenzene. The benzene extracts were taken to dryness to give 485.4 g. ofmaterial which was steam distilled affording 272.5 g. ofα-(3-bromophenyl)propionaldehyde.

A solution of the latter with 465 g. (2.6 moles) of2-cyclohexylmethylpiperidine in 6 liters of benzene was refluxed under aDean-Stark trap for about twelve hours. The solvent was removed in vacuogiving 712.1 g. of an oil which was distilled in vacuo to remove lowerboiling impurities. There was thus obtained as a higher boiling potresidue 357.2 g. of2-cyclohexylmethyl-1-[2-(3-bromophenyl)-1-propenyl]piperidine.

The latter (0.95 mole) was dissolved in 3 liters of hexane, and thesolution cooled in an ice bath and treated with 220 ml. (1.20 moles) of4.9 N ethereal hydrogen chloride. The white gummy solid which separated,consisting of the iminium hydrochloride, was collected, filtered, washedwith fresh hexane, dissolved in 3.5 liters of dimethylformamide, and thesolution treated with 72 g. (1.9 moles) of sodium borohydride added insmall amounts over a ten minute period. The mixture was then stirred atambient temperature for about an hour and a half, treated with one literof 10% sodium hydroxide and 6 liters of water, and then extracted withhexane. The combined hexane extracts afforded 305.4 g. of a yellow oilwhich was distilled in vacuo to give 189.6 g. of material, b.p.143°-161° C./0.06 mm., which was redistilled at 0.5 mm. (b.p. 167°-187°C.) to give 158.5 g. of2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine.

Anal. Calcd. for C₂₁ H₃₂ BrN: C,66.66; H,8.52; Br,21.12. Found: C,66.71;H,8.36; Br,21.20.

A solution of the latter (37.8 g., 0.1 mole) dissolved in 80 ml. ofdiethyl ether was treated dropwise with 165 ml. (0.18 mole) of a 1.08 Msolution of n-butyl lithium in diethyl ether while maintaining thetemperature around 10° C. When addition was complete, the mixture wasstirred for thirty minutes at about 10° C., then at ambient temperaturefor one hour, refluxed for about thirty minutes, cooled once again to10° C., and treated with a solution of 25.8 g. (0.19 mole) of4-methoxybenzaldehyde in 50 ml. of ether while maintaining thetemperature around 15°-20° C. The mixture was then refluxed for twentyminutes, cooled, basified by the addition of 110 ml. of 10% sodiumhydroxide and stirred for ten minutes. The mixture was then filtered,the organic layer separated, and the aqueous layer extracted withadditional diethyl ether. The combined organic extracts were washed withsaturated brine, dried over sodium sulfate, and evaporated to dryness togive 55 g. of an oil which was dissolved in 150 ml. of absolutemethanol. The solution was treated cautiously with 7 g. of sodiumborohydride, stirred at 15° C. for twenty minutes, carefully acidifiedby the addition of 150 ml. of sulfuric acid and extracted three timeswith hexane. The aqueous solution was basified with 150 ml. of 10%sodium hydroxide, diluted with water and extracted four times withhexane. The combined hexane extracts afforded 32 g. of an oil which waschromatographed on 500 g. of alumina using 1.5% isopropylamine in hexaneas eluent. The first 3 liters of eluate were collected and set aside,and the next 3.7 liters collected and evaporated to dryness to give 20.4g. of2-cyclohexylmethyl-1-{2-[3-(α-hydroxy-4-methoxybenzyl)phenyl]propyl}piperidineas a yellow oil.

Anal. Calcd. for C₂₉ H₄₁ NO₂ : C,79.95; H,9.49; N,3.22. Found: C,78.88;H,9.43; N,3.07.

EXAMPLES 3A-3H

Following a procedure similar to that described in Example 3, thefollowing compounds of formula I are prepared:

Example 3A

2-Cyclohexylmethyl-1-{2-[3-(α-hydroxy-3-chlorobenzyl)phenyl]propyl}piperidine(26.8 g. as a yellow oil) prepared by reaction of 37.8 g. (0.1 mole) of2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine with 0.19 moleof n-butyl lithium and reaction of the resulting lithio derivative with28.0 g. (0.2 mole) of 3-chlorobenzaldehyde in about 250 ml. of diethylether.

Anal. Calcd. for C₂₈ H₃₈ ClNO: C,76.42; H,8.70; N,3.18. Found: C,76.64;H,8.98; N,3.16.

Example 3B

2-Cyclohexylmethyl-1-{2-[3-(α-hydroxybenzyl)phenyl]propyl}pyrrolidine(5.3 g. as a tan viscous oil) prepared by reaction of 10.8 g. (0.03mole) of 2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]pyrrolidine with0.06 mole of n-butyl lithium and reaction of the resulting lithioderivative with 7.0 g. (0.066 mole) of benzaldehyde.

Anal. Calcd. for C₃₇ H₃₇ NO: C,82.81; H,9.52; N,3.58. Found: C,82.29;H,10.03; N,3.51.

Example 3C

2-Cyclohexylmethyl-1-{2-[3-(α-hydroxy-3,4-dichlorobenzyl)phenyl]propyl}piperidine(12.3 g. as an oil) prepared by reaction of 37.8 g. (0.1 mole) of2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine with 0.19 moleof n-butyl lithium and reaction of the resulting lithio derivative with35.1 g. (0.2 mole) of 3,4-dichlorobenzaldehyde in diethyl ether.

Example 3D

2-Cyclohexylmethyl-1-{2-[3-(α-hydroxy-2-chlorobenzyl)phenyl]propyl}piperidine(30.7 g. as an oil) prepared by reaction of 37.8 g. (0.1 mole) of2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine with 0.19 moleof n-butyl lithium and reaction of the resulting lithio derivative with28.0 g. (0.2 mole) of 2-chlorobenzaldehyde in diethyl ether.

Example 3E

2-(3-Cyclohexylpropyl)-1-{2-[3-(α-hydroxybenzyl)phenyl]propyl}piperidine(5.4 g. as a viscous oil) prepared by reaction of 12.2 g. (0.03 mole) of2-(3-cyclohexylpropyl)-1-[2-(3-bromophenyl)propyl]piperidine with 0.68mole of n-butyl lithium and reaction of the resulting lithio derivativewith 7.0 g. (0.06 mole) of benzaldehyde in diethyl ether.

Anal. Calcd. for C₃₀ H₄₃ NO: C,83.09; H,9.99; N,3.23. Found: C,82.92;H,10.26; N,3.19.

Example 3F

2-Cyclohexylmethyl-1-{2-[3-(α-hydroxy-4-methylmercaptobenzyl)phenyl]propyl}piperidineprepared by reaction of2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine with n-butyllithium and reaction of the resulting lithio derivative with4-methylmercaptobenzaldehyde.

Example 3G

2-Cyclohexylmethyl-1-{2-[3-(α-hydroxy-4-methylsulfinylbenzyl)phenyl]propyl}piperidineprepared by reaction of2-cyclohexylmethyl-1-{2-[3-(α-hydroxy-4-methylmercaptobenzyl)phenyl]propyl}piperidinedescribed in Example 3F with one molar equivalent amount of hydrogenperoxide in formic acid.

Example 3H

2-Cyclohexylmethyl-1-{2-[3-(α-hydroxy-4-methylsulfonylbenzyl)phenyl]propyl}piperidineprepared by reaction of2-cyclohexylmethyl-1-{2-[3-(α-hydroxy-4-methylmercaptobenzyl)phenyl]propyl}piperidinedescribed in Example 3F with two molar equivalents of hydrogen peroxidein formic acid.

EXAMPLE 4

Following a procedure similar to that described in Example 3, 18.9 g.(0.05 mole) of 2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidinewas reacted with 0.1 mole of n-butyl lithium in diethyl ether and theresulting lithio derivative reacted directly with 12.3 g. (0.103 mole)of 4-methylbenzaldehyde to give 16.9 g. of2-cyclohexylmethyl-1-{2-[3-(α-hydroxy-4-methylbenzyl)phenyl]propyl}piperidineas a yellow oil.

Anal. Calcd. for C₂₉ H₄₁ NO: C,83.00; H,9.85; N,3.34. Found: C,83.04; H,10.01; N,3.31.

EXAMPLE 5

Following a procedure similar to that described in Example 3 above, 18.9g. (0.05 mole) of2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine was reactedwith 0.1 mole of n-butyl lithium in diethyl ether and the resultinglithio derivative reacted directly with 15.5 g. (0.11 mole) of4-chlorobenzaldehyde. The crude product was reduced with 4.5 g. (0.12mole) of sodium borohydride in methanol to give 16.6 g. of2-cyclohexylmethyl-1-{2-[3-(α-hydroxy-4-chlorobenzyl)phenyl]propyl}piperidineas an oil.

Anal. Calcd. for C₂₈ H₃₈ ClNO: C,76.42; H,8.70; Cl,8.06. Found: C,76.82;H,8.76; Cl,8.14.

Following a procedure similar to that described in Example 5, thefollowing compound of formula I was similarly prepared:

Example 5A

2-Cyclohexylmethyl-1-{2-[3-(α-hydroxy-2,6-dichlorobenzyl)phenyl]propyl}piperidine(yellow oil) prepared by reaction of 18.9 g. (0.05 mole) of2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine with 0.1 moleof butyl lithium in diethyl ether followed by 19.2 g. (0.11 mole) of2,6-dichlorobenzaldehyde to give 19.3 g. of product.

Anal. Calcd. for C₂₈ H₃₇ Cl₂ NO: C,70.87; H,7.86; Cl,14.94. Found:C,71.06; H,8.08; Cl,14.81.

EXAMPLE 6

Following a procedure similar to that described in Example 3, 37.8 g.(0.1 mole) of 2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidinewas reacted with 0.18 mole of n-butyl lithium in diethyl ether and theresulting lithio derivative reacted directly with 27 g. (0.23 mole) ofacetophenone to give 11.8 g. of2-cyclohexylmethyl-1-{2-[3-(α-hydroxy-α-methylbenzyl)phenyl]propyl}piperidineas a yellow oil.

Anal. Calcd. for C₂₉ H₄₁ NO: C,83.00; H,9.85; N,3.34. Found: C,83.34;H,9.97; N,3.23.

EXAMPLE 7

A solution of 0.15 mole of n-butyl lithium in 90 ml. of diethyl etherwas prepared by addition of 20.5 g. of n-butyl bromide in 30 ml. ofether to 2.58 g. (0.375 mole) of lithium. Sufficient volume of thesolution to provide 0.093 mole was added to a solution of 19.4 g. (0.051mole) of 2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine(described above in Example 3) in 100 ml. of ether. The mixture wasstirred for thirty minutes while maintaining the temperature below 10°C., refluxed for thirty minutes, cooled once again below 10° C., treatedover a ten minute period with a solution of 13.3 g. (0.10 mole) of4-methoxybenzonitrile in 80 ml. of ether, stirred for an additional hourand a half at below 10° C., then stirred overnight at ambienttemperature and treated with 110 ml. of a solution prepared bydissolving 9 ml. of concentrated sulfuric acid in 45 ml. of water and108 ml. of dioxane. The solution was refluxed for two hours, cooled,basified with 100 ml. of 10% sodium hydroxide, the layers separated, andthe aqueous layer extracted with ether. The ether extracts were washedwith brine, dried and taken to dryness to give 32.6 g. of material whichwas dissolved in hexane and extracted with a solution of 8 ml. ofconcentrated sulfuric acid, 136 ml. of water and 144 ml. of methanol.The extracts were rendered basic with 10% sodium hydroxide, the mixtureextracted once again with hexane, and the hexane extracts washed withbrine, dried and taken to dryness to give 28.1 g. of material which waschromatographed on 400 g. of alumina and eluted with 50% benzene/50%hexane. The first 1750 ml. of eluate was taken to dryness, the residueheated in vacuo at 0.1 mm/220° C. (bath temperature) to drive off some4-methoxybenzonitrile, and the residue once again chromatographed onalumina (250 g.) using 15% ether/85% hexane. The first 400 ml. of eluatewas discarded and the next 1200 ml., on evaporation to dryness, afforded7.1 g. of2-cyclohexylmethyl-1-{2-[3-(4-methoxybenzoyl)phenyl]propyl}piperidine asa yellow oil.

Anal. Calcd. for C₂₉ H₃₉ NO₂ : C,80.33; H,9.07; N,3.23. Found: C,80.50;H,9.17; N,3.14.

EXAMPLES 7A-7L

Following a procedure similar to that described in Examples 3, 4 and 5,the following compounds of formula I are similarly prepared:

Example 7A

2-Cyclohexylmethyl-1-[2-(3-benzoylphenyl)propyl]pyrrolidine, (viscousamber liquid) prepared by reaction of 21.3 g. (0.1 mole) ofα-(3-bromophenyl)propionaldehyde with 31.4 g. (0.2 mole) of2-cyclohexylmethylpyrrolidine in benzene; conversion of the resulting33.7 g. of 1-[2-(3-bromophenyl)-1-propenyl]pyrrolidine to the iminiumchloride with ethereal hydrogen chloride; reduction of the iminiumchloride (34.0 g.) with 6.4 g. (0.17 mole) of sodium borohydride indimethylformamide; reaction of 9.8 g. (0.027 mole) of the resulting(18.8 g.) 2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]pyrrolidine(b.p. 135°-136° C./0.02 mm.) with 0.05 mole of butyl lithium followed by6.2 g. (0.06 mole) of benzonitrile in diethyl ether and decomposition ofthe product with a solution of 4 ml. of concentrated sulfuric acid in 20ml. of water and 50 ml. of dioxane to give 5.1 g. of product.

Anal. Calcd. for C₂₇ H₃₅ NO: C,83.24; H,9.06; N,3.60. Found: C,82.77;H,9.05; N,3.64.

Example 7B

2-Cyclohexylmethyl-1-{2-[3-(4-fluorobenzoyl)phenyl]propyl}piperidine(yellow oil) prepared by reaction of 18.9 g. (0.05 mole) of2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine with 0.1 moleof butyl lithium in diethyl ether followed by 12.8 g. (0.11 mole) of4-fluorobenzonitrile and decomposition of the product with a solution of3.8 ml. of concentrated sulfuric acid in 19 ml. of water and 45 ml. ofdioxane to give 6.5 g. of product.

Anal. Calcd. for C₂₈ H₃₆ FNO: C,79.77; H,8.61; N,3.32. Found: C,79.60;H,8.76; N,3.51.

Example 7C

2-Cyclohexylmethyl-1-{2-[3-(4-methylbenzoyl)phenyl]propyl}piperidine(9.7 g. as a yellow oil) prepared by reaction of 18.9 g. (0.05 mole) of2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine with 0.1 moleof butyl lithium in diethyl ether followed by 12.4 g. (0.11 mole) of4-methylbenzonitrile and decomposition of the product with a solution of3.8 ml. of concentrated sulfuric acid in 19 ml. of water and 45 ml. ofdioxane to give 9.7 g. of product.

Anal. Calcd. for C₂₉ H₃₉ NO: C,83.40; H,9.41; N,3.35. Found: C,83.34;H,9.61; N,3.30.

Example 7D

2-(3-Cyclohexylpropyl)-1-[2-(3-benzoylphenyl)propyl]piperidine (yellowoil) prepared by reaction of 12.2 g. (0.03 mole) of2-(3-cyclohexylpropyl)-1-[2-(3-bromophenyl)propyl]piperidine with 0.06mole of butyl lithium in diethyl ether followed by 7.2 g. (0.07 mole) ofbenzonitrile and decomposition of the product with a solution of 8.3 ml.of concentrated sulfuric acid in 42 ml. of water and 100 ml. of dioxaneto give 6.2 g. of product.

Anal. Calcd. for C₃₀ H₄₁ NO: C,83.47; H,9.57; N,3.24. Found: C,83.28;H,9.77; N,3.05.

Example 7E

2-Cyclohexyl-1-[2-(3-benzoylphenyl)propyl]piperidine (light tan oil)prepared by reaction of 12.7 g. (0.035 mole) of2-cyclohexyl-1-[2-(3-bromophenyl)propyl]piperidine with 0.07 mole ofbutyl lithium in diethyl ether followed by 8.9 g. (0.077 mole) ofbenzonitrile and decomposition of the product with a solution of 9 ml.of concentrated sulfuric acid in 45 ml. of water and 100 ml. of dioxaneto give 6.1 g. of product.

Anal. Calcd. for C₂₇ H₃₅ NO: C,83.24; H,9.06; N,3.60. Found: C,83.16;H,9.16; N,3.44.

Example 7F

2-(2-Cyclohexylethyl)-1-[2-(3-benzoylphenyl)propyl]piperidine (pale tanliquid) prepared by reaction of 13.7 g. (0.035 mole) of2-(2-cyclohexylethyl)-1-[2-(3-bromophenyl)propyl]piperidine with 0.07mole of butyl lithium in diethyl ether followed by 8.9 g. (0.077 mole)of benzonitrile and decomposition of the product with a solution of 9ml. of concentrated sulfuric acid in 45 ml. of water and 100 ml. ofdioxane to give 8.9 g. of product.

Anal. Calcd. for C₂₉ H₃₉ NO: C,83.40; H,9.41; N,3.35. Found: C,83.57;H,9.40; N,3.35.

Example 7G

8-[2-(3-Benzoylphenyl)propyl]-1,4-dioxa-8-azaspiro[4,5]decane (paleyellow oil) prepared by reaction of 10.6 g. (0.05 mole) ofα-(3-bromophenyl)propionaldehyde with 14.3 g. (0.1 mole) of1,4-dioxa-8-azaspiro[4,5]decane in benzene; conversion of the resulting15.7 g. of8-[2-(3-bromophenyl)-1-propenyl]-1,4-dioxa-8-azaspiro[4,5]decane to theiminium chloride with ethereal hydrogen chloride; reduction of theiminium chloride with 3.8 g. (0.08 mole) of sodium borohydride indimethylformamide; reaction of the resulting 17.5 g. (0.05 mole) of8-[2-(3-bromophenyl)propyl]-1,4-dioxa-8-azaspiro[4,5]decane with 0.1mole of butyl lithium followed by 15.5 g. (0.15 mole) of benzonitrile indiethyl ether and decomposition of the product with a solution of 6 ml.of concentrated sulfuric acid in 30 ml. of water and 72 ml. of dioxaneto give 5.1 g. of product.

Anal. Calcd. for C₂₃ H₂₇ NO₃ : C,75.58; H,7.45; N3.83. Found: C,75.60;H,7.69; N,3.87.

Reaction of the free base with a molar equivalent of fumaric acid gave8-[2-(3-benzoylphenyl)propyl]-1,4-dioxa-8-azaspiro[4,5]decane fumarate,m.p. 152°-160° C. (from water).

Example 7H

4-[2-(3-Benzoylphenyl)propyl]morpholine (pale yellow oil) prepared byreaction of 21.3 g. (0.1 mole) of α-(3-bromophenyl)propionaldehyde with17.4 g. (0.2 mole) of morpholine in benzene; conversion of the resulting27.3 g. of 4-[2-(3-bromophenyl)-1-propenyl]morpholine to the iminiumchloride with ethereal hydrogen chloride; reduction of the iminiumchloride with 7.6 g. (0.2 mole) of sodium borohydride indimethylformamide; reaction of the resulting 19 g. of4-[2-(3-bromophenyl)propyl]morpholine (b.p. 99°-120° C./0.09 mm., n_(D)²⁴ =1.5477) with 0.1 mole of butyl lithium followed by 15.5 g. (0.15mole) of benzonitrile in diethyl ether and decomposition of the productwith 150 ml. of a solution made by dissolving 6 ml. of concentratedsulfuric acid in 30 ml. of water and 72 ml. of dioxane to give 7.5 g. ofproduct.

Anal. Calcd. for C₂₀ H₂₃ NO₂ : C,77.64; H,7.49; N,4.53. Found: C,77.62,H,7.37; N,4.71.

A small amount of the free base was converted to the hydrochloride saltto give 4-[2-(3-benzoylphenyl)propyl]morpholine hydrochloridemonohydrate, m.p. 151°-155° C.

Anal. Calcd. for C₂₀ H₂₃ NO₂.HCl.H₂ O: C,66.02; H,7.20; Cl,9.74. Found:C,66.37; H,7.24; Cl,9.59.

The racemic base was resolved into its individual epimers as follows:

In two separate runs, solutions of 3.09 g. (0.01 mole) of the racemicfree base in 25 ml. of ethanol were treated, respectively, with asolution of 3.76 g. (0.01 mole) of (-)-dibenzoyltartaric acidmonohydrate ([α]_(D) ²⁵ =-109.4°/methanol, m.p. 93°-95° C.) and 3.76 g.(0.01 mole) of (+)-dibenzoyltartaric acid monohydrate ([α]_(D) ²⁵=+107°/methanol, m.p. 89°-92° C.). The crystals which separated from thetwo solutions were collected, washed with cold ethanol, then withdiethyl ether and recrystallized from ethanol to give, respectively, 3.7g. ([α]_(D) ²⁵ =-70.0°/methanol, m.p. 141°-141.5° C.) and 2.83 g.([α]_(D) ²⁵ =+70.7°/methanol, m.p. 144°-144.5° C.) of the respectivel-base.l-acid and d-base.d-acid dibenzoyltartrate salts, respectively.

Regeneration of the free bases from the salts by partitioning the latterbetween diethyl ether and aqueous potassium carbonate, isolating thefree bases from the ether extracts and converting the bases to therespective hydrochloride salts gave, respectively,(-)-4-[2-(3-benzoylphenyl)propyl]morpholine hydrochloride, [α]_(D) ²⁵=-9.5°/methanol, m.p. 170°-171° C. and(+)-4-[2-(3-benzoylphenyl)propyl]morpholine hydrochloride, [α]_(D) ²⁵=+13.3°/methanol, m.p. 169°-170° C.

Example 7J

2,6-Dimethyl-4-[2-(3-benzoylphenyl)propyl]morpholinecyclohexanesulfamate prepared by reaction of 21.3 g. (0.1 mole) ofα-(3-bromophenyl)propionaldehyde with 23 g. (0.2 mole) of2,6-dimethylmorpholine in benzene; conversion of the resulting 28.4 g.of 2,6-dimethyl-4-[2-(3-bromophenyl)-1-propenyl]morpholine to theiminium chloride with ethereal hydrogen chloride; reduction of theiminium chloride with 10 g. (0.26 mole) of sodium borohydride indimethylformamide; reaction of the resulting 15.5 g. of2,6-dimethyl-4-[2-(3-bromophenyl)propyl]morpholine (b.p. 125°-129°C./0.01 mm., n_(D) ²⁴ =1.5294) with 0.1 mole of butyl lithium followedby 11 g. (0.11 mole) of benzonitrile in diethyl ether and decompositionof the product with 150 ml. of a solution prepared by dissolving 45 ml.of concentrated sulfuric acid in 225 ml. of water and 540 ml. ofdioxane. The product was converted to the cyclohexanesulfamate saltwhich was recrystallized from acetone to give 7.7 g. of product, m.p.156°-158° C.

Anal. Calcd. for C₂₂ H₂₇ NO₂.C₆ H₁₃ NO₃ S: C,65.08; H,7.80; S,6.20.Found: C,64.86; H,7.72; S,6.22.

Example 7K

2-Cyclohexylmethyl-1-[2-(3-benzoyl-2-methylphenyl)ethyl]piperidineprepared by reaction of 2-bromo-6-bromomethyltoluene [described byLindsay et al., J. Am. Chem. Soc. 83, 943-949 (1961)] with potassiumcyanide in refluxing ethanol; reduction of the resulting(3-bromo-2-methylphenyl)acetonitrile with diisobutylaluminum hydride;reaction of the resulting (3-bromo-2-methylphenyl)acetaldehyde with2-cyclohexylmethylpiperidine in refluxing benzene under a Dean-Starktrap; reduction with sodium borohydride of the iminium hydrochloride ofthe resulting2-cyclohexylmethyl-1-[2-(3-bromo-2-methylphenyl)-1-ethenyl]piperidine;and reaction of the resulting2-cyclohexylmethyl-1-[2-(3-bromo-2-methylphenyl)ethyl]piperidine withn-butyl lithium in diethyl ether followed by reaction of the resultinglithio derivative with benzonitrile.

Example 7L

4-[2-(3-Benzoyl-2-methylphenyl)ethyl]morpholine prepared by reaction of(3-bromo-2-methylphenyl)acetaldehyde with morpholine in refluxingbenzene under a Dean-Stark trap; reduction with sodium borohydride ofthe iminium hydrochloride of the resulting4-[2-(3-bromo-2-methylphenyl)-1-ethenyl]morpholine; and reaction of theresulting 4-[2-(3-bromo-2-methylphenyl)ethyl]morpholine with n-butyllithium in diethyl ether followed by reaction of the resulting lithioderivative with benzonitrile.

EXAMPLE 8

Following a procedure similar to that described in Example 7, 18.9 g.(0.05 mole) of 2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidinewas reacted with 0.095 mole of n-butyl lithium in diethyl ether and theresulting lithio derivative reacted directly with 12.4 g. (0.106 mole)of 2-methylbenzonitrile to give 4.85 g. of2-cyclohexylmethyl-1-{2-[3-(2-methylbenzoyl)phenyl]propyl}piperidine asa yellow oil.

Anal. Calcd. for C₂₉ H₃₉ NO: C,83.40; N,9.41; N,3.35. Found: C,83.14;H,9.54; N,3.67.

EXAMPLE 9

Following a procedure similar to that described in Example 7, 18.9 g.(0.05 mole) of 2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidinewas reacted with 0.095 mole of n-butyl lithium in diethyl ether and theresulting lithio derivative reacted directly with 12.4 g. (0.106 mole)of 3-methylbenzonitrile to give 10.7 g. of2-cyclohexylmethyl-1-{2-[3-(3-methylbenzoyl)phenyl]propyl}piperidine asa yellow oil.

Anal. Calcd. for C₂₉ H₃₉ NO: C,83.40; H,9.41; N,3.35. Found: C,83.06;H,9.38; N,3.48.

EXAMPLE 10

A solution of 13.0 g. (0.032 mole) of2-cyclohexylmethyl-1-{2-[3-(α-hydroxybenzyl)phenyl]propyl}piperidine(described above in Example 1) in 167 ml. of glacial acetic acid and 33ml. of perchloric acid was placed in a Parr hydrogenator and reducedover 3.5 g. of 10% palladium-on-charcoal at ambient temperature under ahydrogen pressure of 54 p.s.i. When reduction was complete, the catalystwas removed by filtration, the filtrate was taken to dryness, and theresidue rendered basic with 10% sodium hydroxide and extracted fourtimes with hexane. The combined hexane extracts were dried, taken todryness, and the residue chromatographed on 220 g. of alumina, andeluted with 10% ether/89% hexane/1% isopropylamine. The first 350 ml. ofeluate when taken to dryness afforded 10.6 g. of2-cyclohexylmethyl-1-[2-(3-benzylphenyl)propyl]piperidine as a yellowoil.

Anal. Calcd. for C₂₈ H₃₉ N: C,86.32; H,10.09; N,3.59. Found: C,86.18;H,10.34; N,3.51.

EXAMPLE 11

Following a procedure similar to that described in Example 10, 11.1 g.(0.027 mole) of2-cyclohexylmethyl-1-{2-[3-(α-hydroxy-α-methylbenzyl)phenyl]propyl}piperidine(described in Example 6) dissolved in 180 ml. of glacial acetic acidover 20 ml. of 72% perchloric acid was reduced with hydrogen over 0.8 g.of palladium-on-charcoal to give 10.3 g. of2-cyclohexylmethyl-1-{2-[3-(α-methylbenzyl)phenyl]propyl}piperidine as ayellow oil.

Anal. Calcd. for C₂₉ H₄₁ N: C,86.29; H,10.24; N,3.47. Found: C,86.04;H,10.21; N,3.70.

EXAMPLE 12

A solution of 26.8 g. (0.066 mole) of2-cyclohexylmethyl-1-{2-[3-(α-hydroxybenzyl)phenyl]propyl}piperidine(described above in Example 1) in 140 ml. of benzene was vigorouslystirred and cooled to 16° C. and then treated dropwise over a period often minutes with 58 ml. of a solution prepared by dissolving 26.7 g. ofchromium trioxide in 23 ml. of concentrated sulfuric acid and dilutingwith water to 100 ml. The mixture was stirred with cooling for about onehour and forty-five minutes, the benzene layer removed, and the aqueouslayer made basic by addition of 120 ml. of 10% sodium hydroxide andextracted with benzene. The organic extracts, on washing once withdilute alkali, once with brine, and evaporation to dryness, afforded21.8 g. of an oil which was chromatographed over 300 g. of alumina using3% isopropylamine in hexane as eluent. The first 600 ml. of eluate wascollected and taken to dryness to give 16.2 g. of2-cyclohexylmethyl-1-[2-(3-benzoylphenyl)propyl]piperidine as a paleyellow viscous oil.

Anal. Calcd. for C₂₈ H₃₇ NO: C,83.33; H,9.23; N,3.47. Found: C,83.30;H,9.33; N,3.45.

EXAMPLE 13

Following a procedure similar to that described in Example 12, 15.2 g.(0.39 mole) of2,6-dimethyl-1-{2-[3-(α-hydroxybenzyl)phenyl]propyl}piperidine(described above in Example 2) was oxidized with 34 ml. of a solutionprepared by dissolving 13.4 g. of chromium trioxide in 11.5 ml. ofconcentrated sulfuric acid and dilution with water to 50 ml. Theproduct, in the form of the free base, was purified by chromatographingon alumina using 10% ether/3% isopropylamine/87% hexane as eluent. Therewas thus obtained 4.8 g. of2,6-dimethyl-1-[2-(3-benzoylphenyl)propyl]piperidine as a colorlessviscous oil.

Anal. Calcd. for C₂₃ H₂₉ NO: C,82.34; H,8.71; N,4.18. Found: C,82.23;H,8.82; N,4.15.

EXAMPLES 13A-13G

Proceeding in a manner similar to that described in Examples 1 and 12,the following compounds of formula I are obtained:

Example 13A

2-Methyl-1-[2-(3-benzoylphenyl)propyl]hexamethyleneimine prepared byreaction of α-(3-benzoylphenyl)propionyl chloride with2-methylhexamethyleneimine [Mueller et al., Monatsh. 61, 212-218(1932)]; reduction with lithium aluminum hydride of the resulting2-methyl-1-[α-(3-benzoylphenyl)propionyl]hexamethyleneimine; and chromicacid oxidation of the resulting2-methyl-1-{2-[3-(α-hydroxybenzyl)phenyl]propyl}hexamethyleneimine.

Example 13B

4-Cyclohexyl-1-[2-(3-benzoylphenyl)propyl]piperidine prepared byreaction of α-(3-benzoylphenyl)propionyl chloride with4-cyclohexylpiperidine; reduction with lithium aluminum hydride of theresulting 4-cyclohexyl-1-[α-(3-benzoylphenyl)propionyl]piperidine; andchromic acid oxidation of the resulting4-cyclohexyl-1-{2-[3-(α-hydroxybenzyl)phenyl]propyl}piperidine.

Example 13C

3-Butyl-4-[2-(3-benzoylphenyl)propyl]morpholine prepared by reaction ofα-(3-benzoylphenyl)propionyl chloride with 3-butylmorpholine; reductionwith lithium aluminum hydride of the resulting3-butyl-4-[α-(3-benzoylphenyl)propionyl]morpholine; and chromic acidoxidation of the resulting3-butyl-4-{2-[3-(α-hydroxybenzyl)phenyl]propyl}morpholine.

Example 13D

3-Ethyl-4-[2-(3-benzoylphenyl)propyl]thiomorpholine prepared by reactionof α-(3-benzoylphenyl)propionyl chloride with 3-ethylthiomorpholine;conversion of the resulting3-ethyl-4-[α-(3-benzoylphenyl)propionyl]thiomorpholine to thecorresponding ethylene glycol ketal; reduction with lithium aluminumhydride of the resulting ketal; and hydrolysis with dilute mineral acidof the resulting 3-ethyl-4-[2-(3-benzoylphenyl)propyl]thiomorpholineethylene glycol ketal.

Example 13E

4-Methyl-1-[2-(3-benzoylphenyl)propyl]piperazine prepared by reaction ofα-(3-benzoylphenyl)propionyl chloride with 1-methylpiperazine; reductionwith lithium aluminum hydride of the resulting4-methyl-1-[α-(3-benzoylphenyl)propionyl]piperazine; and chromic acidoxidation of the resulting4-methyl-1-{2-[3-(α-hydroxybenzyl)phenyl]propyl}piperazine.

Example 13F

3-Benzyl-1-[2-(3-benzoylphenyl)propyl]piperidine prepared by reaction ofα-(3-benzoylphenyl)propionyl chloride with 3-benzylpiperidine; reductionwith lithium aluminum hydride of the resulting3-benzyl-1-[α-(3-benzoylphenyl)propionyl]piperidine; and chromic acidoxidation of the resulting3-benzyl-1-{2-[3-(α-hydroxybenzyl)phenyl]propyl}piperidine.

Example 13G

N-[5-(N',N'-Dimethylamino)-2-pentyl]-N-[2-(3-benzoylphenyl)propyl]amineprepared by reaction of α-(3-benzoylphenyl)propionyl chloride with5-(N',N'-dimethylamino)-2-pentylamine; reduction with lithium aluminumhydride of the resultingN-[5-(N',N'-dimethylamino-2-pentyl]-N-[α-(3-benzoylphenyl)propionyl]amine;and chromic acid oxidation of the resultingN-[5-(N',N'-dimethylamino-2-pentyl]-N-{2-[3-(α-hydroxybenzyl)phenyl]propyl}amine.

EXAMPLE 14

Following a procedure similar to that described in Example 7, 5.0 g.(13.2 mole) of 2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidinewas reacted with 0.026 mole of n-butyl lithium in diethyl ether and theresulting lithio derivative reacted directly with benzonitrile to give4.0 g. of 2-cyclohexylmethyl-1-[2-(3-benzoylphenyl)propyl]piperidineidentical with the material described in Example 12.

A diastereoisomer of the same compound was prepared by the followingprocedure. The 2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidinedescribed above in Example 3 (77.3 g.) was converted to thehydrochloride salt by dissolving the base in 100 ml. of acetone andtreating the solution with 70 ml. of etherea hydrogen chloride. Thesolvent was evaporated in vacuo and the residue treated with another 100ml. of acetone and again evaporate to dryness. The residue wasrecrystallized from 125 ml. of acetone and 150 ml. of ether, and thesolid which separated after standing for about twenty-four hours atabout 0° C. was collected, washed with acetone and dried to give 30.7 g.of the corresponding hydrochloride salt, m.p. 193°-196° C. Furtherrecrystallization from 350 ml. of acetonitrile afforded 23.9 g. of thepurified diastereoisomer, having m.p. 197°-201° C. An 18.4 g. portion ofthe latter was reconverted to the free base by cleavage with dilutealkali, extraction of the base into hexane and evaporation of the hexaneextracts to dryness.

The resulting free base (15.1 g., 0.04 mole) was converted to the lithioderivative by reaction with 0.08 mole of n-butyl lithium in diethylether (concentration 1.04 mmole/ml.), and the resulting lithiumderivative was reacted directly with 8.75 g. (0.085 mole) ofbenzonitrile in 35 ml. of diethyl ether using the procedure describedabove in Example 7. The product was isolated by distilling the crudeproduct in vacuo and chromatographing the portion of sample which wouldnot distill at an oil bath temperature of 240° C. at 0.10 mm. Theproduct thus obtained was converted to the hydrochloride salt which wasrecrystallized from acetone/diethyl ether to give 4.38 g. of2-cyclohexylmethyl-1-[2-(3-benzoylphenyl)propyl]piperidinehydrochloride, m.p. 155°-157° C., one of the possible diastereoisomersof the compound described above.

Anal. Calcd. for C₂₈ H₃₇ NO.HCl: C,76.42; H,8.70; Cl,8.06. Found:C,76.22; H,8.67; Cl,8.16.

Following a procedure similar to that described in Example 14, thefollowing compound of formula I was similarly prepared:

Example 14A

1-[2-(3-Benzoylphenyl)propyl]piperidine hydrochloride (m.p. 151°-153° C.from acetone) prepared by reaction of 16.3 g. (0.057 mole) of1-[2-(3-bromophenyl)propyl]piperidine with 0.12 mole of butyl lithium indiethyl ether followed by 12.6 g. (0.12 mole) of benzonitrile anddecomposition of the product with a solution of 45 ml. of concentratedsulfuric acid in 225 ml. of water and 540 ml. of dioxane to give 6.5 g.of product.

Anal. Calcd. for C₂₁ H₂₅ NO.HCl: C,73.34; H,7.62; Cl,10.31. Found:C,72.70; H,7.92; Cl,10.32.

EXAMPLE 15

A mixture of 37.5 g. (0.093 mole) of2-cyclohexylmethyl-1-[2-(3-benzoylphenyl)propyl]piperidine (described inExamples 12 and 14 above) and 10.0 g. (0.14 mole) of hydroxylamine in125 ml. of 95% ethanol and 25 ml of water was treated with stirring with19.4 g. of powdered sodium hydroxide and the mixture refluxed for a halfhour. The mixture was then cooled, diluted with hexane, the aqueouslayer separated, and the organic layer, after drying, was evaporated todryness to give 41.6 g. of a yellow oil which was chromatographed onalumina in 30:70 diethyl ether/hexane to give 37.3 g. of2-cyclohexylmethyl-1-[2-(3-benzoylphenyl)propyl]piperidine oxime as anoil.

Anal. Calcd. for C₂₈ H₃₈ N₂ O: C,80.33; H,9.15; N,6.69. Found: C,80.03;H,9.42; N,6.44.

EXAMPLES 15A-15C

Following a procedure similar to that described in Example 15, thefollowing compounds of formula I were similarly prepared:

Example 15A

4-[2-(3-Benzoylphenyl)ethyl]morpholine oxime (m.p. 117°-134° C., frombenzene/hexane) prepared by reacting 18.15 g. (0.05 mole) of4-[2-(3-benzoylphenyl)ethyl]morpholine hydrochloride with 5.6 g. (0.08mole) of hydroxylamine hydrochloride in the presence of 12.5 g. (0.31mole) of sodium hydroxide in 70 ml. of ethanol and 18.5 ml. of water togive 14.06 g. of product.

Anal. Calcd. for C₁₉ H₂₂ N₂ O₂ : C,73.52; H,7.14; N,9.03. Found:C,73.79; H,7.26; N,8.72.

Example 15B

4-(3-Benzoylphenyl)methylmorpholine oxime (m.p. 145°-167° C.) preparedby reaction of 28.62 g. (0.09 mole) of4-(3-benzoylphenyl)methylmorpholine hydrochloride with 9.63 g. (0.14mole) of hydroxylamine hydrochloride in the presence of 21.68 g. (0.54mole) of sodium hydroxide in 35 ml. of ethanol and 27 ml. of water togive 13.9 g. of product.

Example 15C

4-[2-(3-Benzoylphenyl)propyl]morpholine oxime (m.p. 117°-130° C., fromisopropanol) prepared by reaction of 27 g. (0.078 mole) of4-[2-(3-benzoylphenyl)propyl]morpholine hydrochloride with 8.2 g. (0.117mole) of hydroxylamine hydrochloride in the presence of 18.8 g. (0.47mole) of sodium hydroxide in 115 ml. of ethanol and 27 ml. of water togive 3.2 g. of product.

EXAMPLE 16

A solution of 17 g. (0.041 mole) of the2-cyclohexylmethyl-1-[2-(3-benzoylphenyl)propyl]piperidine oximedescribed above in Example 15 in 110 ml. of ethanol was brought toreflux and treated with 10 g. (0.043 mole) of sodium metal, added insmall pieces. Refluxing was continued until all sodium had dissolved,and the solution was then cooled, diluted with 140 ml. of water,evaporated to a volume of about 150 ml. in vacuo, and then extractedwith three portions of benzene. Evaporation of the benzene extracts todryness afforded 14.2 g. of an oil which was converted to the acetatesalt by dissolving in chloroform, adding glacial acetic acid andevaporation to dryness. The acetate salt was again dissolved inchloroform and chromatographed on alumina, eluting with chloroform. Theacetate hydrolyzed on the column, and the free base obtained from theeluate was dissolved in ethanol, and the solution acidified withethereal hydrogen chloride and evaporated to dryness to give 6.38 g. of2-cyclohexylmethyl-1-{2-[3 -(α-aminobenzyl)phenyl]propyl}piperidinedihydrochloride, m.p. 167°-195° C.

Anal. Calcd. for C₂₈ H₄₁ N₂.2HCl: N,5.87; Cl,14.85. Found: N,5.61;Cl,14.66.

EXAMPLES 16A-16C

Following a procedure similar to that described in Example 16, thefollowing compounds of formulas I and Ia were similarly prepared:

Example 16A

4-{2-[3-(α-Aminobenzyl)phenyl]ethyl}morpholine dihydrochloride, m.p.260°-263° C. (15.42 g. from methanol/diethyl ether) prepared by reducing14.55 g. (0.047 mole) of 4-[2-(3-benzoylphenyl)ethyl]morpholine oximewith 11.5 g. (0.50 mole) of sodium in 100 ml. of absolute ethanol.

Anal. Calcd. for C₁₉ H₂₄ N₂ O.2HCl: C,61.79; H,7.10; Cl,19.20. Found:C,61.88; H,6.90; Cl,19.16.

Example 16B

4-{[3-(α-Aminobenzyl)phenyl]methyl}morpholine dihydrochloridemonohydrate, m.p. 270°-274° C. (8.3 g., from methanol/ether) prepared byreduction of 8.12 g. (0.027 mole) of4-[(3-benzoylphenyl)methyl]morpholine oxime with 6.45 g. (0.28 mole) ofsodium in absolute ethanol.

Anal. Calcd. for C₁₈ H₂₂ N₂ O.2HCl.H₂ O: C,60.84; H,6.81; Cl,19.96.Found: C,60.68; H,6.83; Cl,20.27.

Example 16C

4-{2-[3-(α-Aminobenzyl)phenyl]propyl}morpholine dihydrochloride m.p.255°-265° C. (9.5 g., from methanol/diethyl ether) prepared by reductionof 10.0 g. (0.03 mole) of 4-[2-(3-benzoylphenyl)propyl]morpholine oximewith 7.1 g. (0.31 mole) of sodium in 65 ml. of absolute ethanol.

Anal. Calcd. for C₂₀ H₂₆ N₂ O.2HCL: C,62.66; H,7.36; Cl,18.50. Found:C,61.78; H,7.17; Cl,18.01.

EXAMPLE 17

A solution of 13.0 g. (0.031 mole) of2-cyclohexylmethyl-1-{2-[3-(α-hydroxy-α-methylbenzyl)phenyl]propyl}piperidine(described in Example 6) in 130 ml. of methanol and 3 ml. ofconcentrated sulfuric acid was stirred and refluxed for forty-fiveminutes, then cooled, diluted with 100 ml. of water, basified with 5 ml.of 35% sodium hydroxide and extracted with hexane. The combined hexaneextracts, on washing with brine, drying and evaporation to dryness gave14.2 g. of an oil which was chromatographed on 260 g. of alumina in 8:92diethyl ether/hexane. There was thus obtained 9.8 g. of2-cyclohexylmethyl-1-{2-[3-(1-phenyl-1-vinyl)phenyl]propyl}piperidine asan oil.

Anal. Calcd. for C₂₉ H₃₉ N: C,86.72; H,9.79; N,3.49. Found: C,86.79;H,9.76; N,3.28.

EXAMPLE 18

4-Methoxyphenylacetic acid (41.5 g., 0.25 mole) was converted to thecorresponding acid chloride with 47.7 g. (0.4 mole) of thionyl chloridein benzene using the procedure described above in Example 1. The acidchloride thus produced (36.8 g., 0.2 mole) was reacted with 24.1 g.(0.21 mole) of 2,6-dimethylpiperidine in ether in the presence of 24.2g. (0.24 mole) of triethylamine using the procedure described above inExample 1. The resulting2,6-dimethyl-1-[(4-methoxyphenyl)acetyl]piperidine (38.8 g., 0.15 mole)was reduced with lithium aluminum hydride and the product isolated inthe form of the hydrochloride salt to give 15.32 g. of2,6-dimethyl-1-[2-(4-methoxyphenyl)ethyl]piperidine hydrochloride, m.p.195°-200° C.

The latter (1.0 g., 0.004 mole), in the form of the free base, was addedin small portions to a stirred mixture of 1.21 g. (0.009 mole) ofaluminum chloride and 1.28 g. (0.009 mole) of benzoyl chloride. Theresulting viscous mixture was stirred for about twelve hours at ambienttemperature and then mixed with ice, 2 ml. of concentrated hydrochloricacid and 2 ml. of water. The resulting mixture was extracted withchloroform, and the chloroform extracts washed with brine, dried andevaporated to dryness to give2,6-dimethyl-1-[2-(3-benzoyl-4-methoxyphenyl)ethyl]piperidine as ayellow oil.

EXAMPLE 19

A mixture of 45 g (0.13 mole) of2,6-dimethyl-1-[2-(3-benzoyl-4-methoxyphenyl)ethyl]piperidine (describedabove in Example 18) and 34.9 g. (0.26 mole) of aluminum chloride intetrachloroethane was heated and stirred at 50° C. for about twelvehours and then poured into a solution of 30 ml. of concentratedhydrochloric acid and 30 ml. of ice water. The mixture was basified withsodium carbonate, extracted four times with chloroform, and thechloroform extracts washed with saturated brine, dried and evaporated todryness to give crude product which was once again heated for twelvehours at 50° C. with 30 g. of aluminum chloride and 30 ml. oftetrachloroethane. On working up as before, there was obtained 8 g. ofcrude material which was dissolved in chloroform. The organic solutionwas washed five times with 10% sodium carbonate, once with brine, thendried and taken to dryness. The residue was dissolved in acetone, andthe solution was treated with ethereal hydrogen chloride to give solidmaterial which was recrystallized from isopropanol. There was thusobtained 5.8 g. of2,6-dimethyl-1-[2-(3-benzoyl-4-hydroxyphenyl)ethyl]piperidinehydrochloride, m.p. 217°-219° C.

Anal. Calcd. for C₂₂ H₂₇ NO₂.HCl: C,70.67; H,7.55; N,3.75. Found:C,70.87; H,7.58; N,3.73.

EXAMPLE 20

A solution of 13.2 g. (0.03 mole) of2-cyclohexylmethyl-1-{2-[3-(α-hydroxy-4-chlorobenzyl)phenyl]propyl}piperidine(described above in Example 5), 16 ml. of concentrated nitric acid and32 ml. of 50% perchloric acid in 160 ml. of 1,2-dimethoxyethane washeated under reflux for one and a quarter hours, then cooled, dilutedwith 50 ml. of water, basified with 150 ml. of 10% sodium hydroxide andextracted with hexane. The hexane extracts were washed once with water,once with brine, dried and evaporated to dryness to give 12 g. of crudeproduct which was chromatographed on 200 g. of alumina using 10:90ether/hexane as eluent. The first 75 ml. of eluate was discarded and thenext 600 ml. was taken to dryness to yield 9.2 g. of2-cyclohexylmethyl-1-{2-[3-(4-chlorobenzoyl)phenyl]propyl}piperidine.

Anal. Calcd. for C₂₈ H₃₆ ClNO: C,76.77; H,8.28; Cl,8.09. Found: C,76.85;H,8.35; Cl,8.27.

EXAMPLES 20A-20D

Following a procedure similar to that described in Example 20, thefollowing compounds of formula I were similarly prepared:

EXAMPLE 20A

2-Cyclohexylmethyl-1-[2-(3-benzoylphenyl)ethyl]piperidine (yellow oil)prepared by oxidation of 14.0 g. (0.03 mole) of2-cyclohexylmethyl-1-{2-[3-(α-hydroxybenzyl)phenyl]ethyl}piperidine(described above in Example 1A) in 227 ml. of a solution prepared bydissolving 44.5 ml. of 72% perchloric acid, 20 ml. of water and 32 ml.of concentrated nitric acid in 320 ml. of 1,2-dimethoxyethane. There wasthus obtained 8.74 g. of product.

Anal. Calcd. for C₂₇ H₃₅ NO: C,83.24; H,9.06; N,3.60. Found: C,83.46;H,9.26; N,3.75.

EXAMPLE 20B

2-Cyclohexylmethyl-1-{2-[3-(3-chlorobenzoyl)phenyl]propyl}piperidine(yellow oil) prepared by oxidation of 17.0 g. (0.039 mole) of2-cyclohexylmethyl-1-{2-[3-(α-hydroxyl-3-chlorobenzyl)phenyl]propyl}piperidine(described above in Example 3A) in 244 ml. of a solution prepared bydissolving 48 ml. of 50%. perchloric acid and 24 ml. of concentratednitric acid in 240 ml. of 1,2-dimethoxyethane. There was thus obtained9.65 g. of product.

Anal. Calcd. for C₂₈ H₃₆ ClNO: C,76.77; H,8.28; N,3.20. Found: C,76.86;H,8.36; N,3.13.

EXAMPLE 20C

2-Cyclohexylmethyl-1-{2-[3-(3,4-dichlorobenzoyl)phenyl]propyl}piperidine(yellow oil) prepared by oxidation of 11.9 g. (0.25 mole) of2-cyclohexylmethyl-1-{2-[3-(α-hydroxy-3,4-dichlorobenzyl)phenyl]propyl}piperidine(described above in Example 3C) in 156 ml. of a solution prepared bydissolving 24 ml. of 50% perchloric acid and 12 ml. of concentratednitric acid in 120 ml. of 1,2-dimethoxyethane. There was thus obtained5.2 g. of product.

Anal. Calcd. for C₂₈ H₃₅ Cl₂ NO: C,71.18; H,7.47; N,2,96. Found:C,71.47; H,7.82; N,2,96.

EXAMPLE 20D

2-Cyclohexylmethyl-1-{2-[3-(2-chlorobenzoyl)phenyl]propyl}piperidine(yellow oil) prepared by oxidation of 15.7 g. (0.036 mole) of2-cyclohexylmethyl-1-{2-[3-(α-hydroxy-2-chlorobenzyl)phenyl]propyl}piperidine(described above in Example 3D) in 225 ml. of a solution prepared bydissolving 48 ml. of 50% perchloric acid and 24 ml. of concentratednitric acid in 240 ml. of 1,2-dimethoxyethane. There was thus obtained6.4 g. of product.

Anal. Calcd. for C₂₈ N₃₆ ClNO: C,76.77; H,8.28; N,3.20. Found: C,76.47;H,8.58; N,3.09.

EXAMPLE 21

A solution of 11.0 g. (0.126 mole) of morpholine in 24 ml. ofdimethylformamide was stirred with external cooling in a water bath andtreated over a ten minute period with a solution of 17.35 g. (0.06 mole)of 1-(3-benzoylphenyl)-1-bromoethane in 24 ml. of dimethylformamide.When addition was complete the mixture was stirred for an additionalhour at ambient temperature. The mixture was then filtered, the filterwashed with ether, the filtrate poured into 125 ml. of water and themixture extracted twice with ether. Isolation of the product in the formof the free base from the ether extracts in the conventional mannerafforded 14.8 g. of oily product which was chromatographed on aluminausing a 1:1 ether:hexane solution as eluent to give 12 g. of4-[1-(3-benzoylphenyl)ethyl]morpholine as a pale yellow oil.

Anal. Calcd. for C₁₉ H₂₁ NO₂ : C,77.26; H,7.17; N,4.74. Found: C,76.95;H,7.11; N,4.61.

EXAMPLE 22

4-{2-[3-(α-Aminobenzyl)phenyl]ethyl}morpholine (15.6 g., 0.05 mole,described in Example 16A) was mixed with 13.8 g. (0.30 mole) of 97%formic acid and 9.4 g. (0.11 mole) of 35% formaldehyde solution. Themixture was heated to 95° C. to effect complete solution of the gummybase, heating was continued for ten hours, and the solution was cooledand poured into a dilute sodium hydroxide/ice mixture. Isolation of theorganic material in the usual manner by extraction with ether afforded15.6 g. of an oil which was chromatographed on 400 g. of alumina using1.5:98.5 isopropylamine:hexane as eluent. The first ten fractions, 75ml. each, were collected and set aside, and the next ten fractions,75-100 ml. each, were combined and taken to dryness to give 10.6 g. of4-{2-[3-(α-dimethylaminobenzyl)phenyl]ethyl}morpholine as an oil whichcrystallized on standing, m.p. 60°-63° C.

Anal. Calcd. for C₂₁ H₂₈ N₂ O: C,77.74; H,8.70; N,8.63. Found: C,77.20;H,8.60; N,8.48.

EXAMPLE 23

Reaction of the2-cyclohexylmethyl-1-{2-[3-(4-methoxybenzoyl)phenyl]propyl}piperidinedescribed above in Example 7 with hydrobromic acid in glacial aceticacid, and isolation of the product from a neutral medium affords2-cyclohexylmethyl-1-{2-[3-(4-hydroxybenzoyl)phenyl]propyl}piperidine.

EXAMPLES 24A-24M

Example 24A

A mixture of 23 g. (1.0 mole) of sodium cut into small pieces in 1.2liters of isopropanol was stirred and refluxed until all solid haddissolved. The mixture was then cooled to room temperature and treatedwith a solution of 159.2 g. (0.8 mole) of 4-bromoacetophenone and 122.5g. (1.0 mole) of ethyl chloroacetate in 200 ml. of isopropanol. Themixture was stirred in an ice bath for seventeen hours during which timethe temperature of the reaction mixture gradually rose to roomtemperature as the ice melted. Removal of the solvent in vacuo affordeda dark brown residual oil which was dissolved in 500 ml. of benzene andwashed twice with cold water and then with saturated brine. The organicsolution, on filtration, drying and evaporation to dryness afforded adark brown oil which was distilled in vacuo to give 227.2 g. of ethyl2-methyl-2-(4-bromophenyl)glycidate, b.p. 96°-113° C./0.08 mm.

A mixture of the latter (226 g., 0.8 mole) in a solution of 36.8 g.(0.92 mole) of sodium hydroxide in 200 ml. of water and 200 ml ofethanol was heated under reflux for eighteen hours and the solventremoved in vacuo. The residue was dissolved in 700 ml. of water andextracted two times with 100 ml. portions of benzene. The aqueoussolution was filtered, acidified with 90 ml. of concentratedhydrochloric acid and the mixture steam distilled. The distillate wasextracted with methylene dichloride, and the extracts were filtered,dried, and taken to dryness in vacuo to give 126 g. of a pale yellow oilwhich was distilled in vacuo to give 125 g. ofα-(4-bromophenyl)propionaldehyde, b.p. 61°-65° C./0.08-0.13 mm.

A solution of 42.6 g. (0.2 mole) of the latter in 400 ml. of absolutemethanol was treated with 15.14 g. (0.40 mole) of sodium borohydride,added in portions over a period of about twenty minutes, whilemaintaining the temperature around 20° C. The mixture was stirred forabout four hours, then treated with 40-50 ml. of acetone and evaporatedto dryness in vacuo. The residue was shaken with a mixture of 250 ml. ofbenzene and 350 ml. of 25% aqueous potassium hydroxide, and the organiclayer was washed with water, then with brine, dried and evaporated todryness to give 59.56 g. of an oil which was distilled in vacuo to give38.1 g. of 2-(4-bromophenyl)propanol, b.p. 109°-117° C./0.04 mole.

The latter was dissolved in about a three molar excess of dihydropyran,the mixture was treated with about seven drops of concentratedhydrochloric acid, and the solution allowed to stand at ambienttemperature for about eighteen hours. The mixture was then treated withsolid sodium bicarbonate to decompose the acid present, the excesssolvent was removed in vacuo, and the residue was distilled in vacuo togive 38.0 g. of 2-(4-bromophenyl)propanol tetrahydropyranyl ether, b.p.118°-124° C./0.3 mm., n_(D) ²³ =1.5305.

A solution of the latter (17.9 g., 0.06 mole) in 150 ml. of anhydrousdiethyl ether was treated with 35.0 ml. of a 2.04 M solution of n-butyllithium in hexane, and the solution was stirred at -10° to -5° C. forabout forty-five minutes, then at about 0° to 25° C. for about twohours. The mixture was then cooled to -10° C. and treated over a fifteenminute period at -10° to -5° C. with a solution of 8.2 g. (0.08 mole) ofbenzonitrile in 50 ml. of anhydrous diethyl ether. The miture wasstirred in an ice bath for five hours, then for about twelve hours atambient temperature. The mixture was once again cooled to about 5° C.and treated with 75 ml. of 6 N hydrochloric acid and 75 ml. of water,and the two-phase system was stirred and heated under reflux for aboutthree and a half hours. The mixture was filtered, the organic phase wasseparated from the aqueous phase, and the latter was extracted withadditional portions of diethyl ether. The combined ether extracts werewashed with water, then with brine, filtered, dried and evaporated todryness to give 13.95 g. of an oil which was distilled in vacuo to give7.70 g. of 2-(4-benzoylphenyl)propanol, b.p. 165.5° C./0.04 mm; n_(D) ²⁴=1.5930.

A solution of 7.20 g. (0.03 mole) of the latter in 20 ml. of drypyridine was treated with a solution of 6.66 g. (0.30 mole) ofp-toluenesulfonyl chloride in 25 ml. of pyridine, and the solution wasallowed to stand at ambient temperature for about twenty hours. Themixture was then evaporated in vacuo to a volume of about 20 ml., thendiluted with 200 ml. of water and extracted with diethyl ether. Theether extracts were washed first with water, then with dilutehydrochloric acid, then with dilute potassium hydroxide, once again withwater, filtered, dried and evaporated to dryness to give a viscous oilweighing 11.2 g. The latter was crystallized from hexane to give 9.09 g.of 2-(4-benzoylphenyl)propyl p-toluenesulfonate, m.p. 79°-81° C.

A solution of 11.8 g. (0.03 mole) of the latter and 10.4 g. (0.12 mole)of morpholine in 250 ml. of acetonitrile was heated under reflux forfifty-three hours and then taken to dryness in vacuo, the last traces ofmorpholine being removed by heating under high vacuum for several hours.The residue was partitioned between diethyl ether and water, the aqueouslayer was washed several times with additional portions of ether, andthe combined ether extracts were dried and taken to dryness. The residuewas dissolved in diethyl ether, the solution was treated with etherealhydrogen chloride, and the solid which separated was collected andrecrystallized from acetone to give 9.5 g. of4-[2-(4-benzoylphenyl)propyl]morpholine hydrochloride, m.p. 207°-208° C.

Following a procedure similar to that described in Example 24A, thefollowing compounds of formula I were prepared:

EXAMPLE 24B

Reaction of 11.8 g. (0.03 mole) of 2-(4-benzoylphenyl)propylp-toluenesulfonate with 12.3 g. (0.09 mole) of1,4-dioxa-8-azaspiro[4,5]decane in 250 ml. of acetonitrile and isolationof the product in the form of the hydrochloride salt gave 12.4 g. of8-[2-(4-benzoylphenyl)propyl]1,4-dioxa-8-azaspiro[4,5]decanehydrochloride, m.p. 211°-212° C. (from diethyl ether).

EXAMPLE 24C

Reaction of 2-(4-benzoylphenyl)propyl p-toluenesulfonate with1-benzylpiperazine in acetonitrile and isolation of the product in theform of the free base affords1-[2-(4-benzoylphenyl)propyl]-4-benzylpiperazine. Conversion of thelatter to the ethylene glycol ketal, catalytic reduction of the latterover palladium-on-charcoal at a hydrogen pressure of 50 p.s.i. in orderto effect catalytic debenzylation thereof using the manipulativeprocedure described in Example 10 above, cleavage of the ketal withaqueous hydrochloric acid, and isolation of the product in the form ofthe dihydrochloric salt affords 1-[2-(4-benzoylphenyl)propyl]piperazinedihydrochloride m.p. 243°-245° C. (from ethanol).

EXAMPLE 24D

Reaction of 11.7 g. (0.03 mole) of 2-(4-benzoylphenyl)propylp-toluenesulfonate with 9.30 g. (0.09 mole) of thiomorpholine in 45 ml.of acetonitrile and isolation of the product in the form of thehydrochloride salt gave 6.7 g. of4-[2-(4-benzoylphenyl)propy]thiomorpholine hydrochloride, m.p. 197°-198°C. (from acetone).

EXAMPLE 24E

A solution of 76.8 g. (0.5 mole) of 4,4-dihydroxypiperidinehydrochloride, 50.0 g. (0.54 mole) of 1,2-ethanedithiol and 0.3 g. ofp-toluenesulfonic acid in 600 ml. of toluene was refluxed with stirringunder a Dean-Stark water trap until no further water was given off. Thesolid which separated from the reaction mixture was collected,partitioned between aqueous saturated potassium carbonate solution andchloroform, the chloroform separated, and the aqueous layer wasextracted with additional portions of chloroform. The combinedchloroform extracts were dried and taken to dryness to give 65.63 g. ofan oil which was distilled in vacuo to give 14.94 g. of1,4-dithia-8-azaspiro[4,5]decane, b.p. 128°-154° C./18-20 mm., n_(D) ²³=1.5856.

Reaction of 12.74 g. (0.073 mole) of the latter with 9.56 g. (0.024mole) of 2-(4-benzoylphenyl)propyl p-toluenesulfonate in 100 ml. ofacetonitrile and isolation of the product in the form of thehydrochloride salt gave 8.65 g. of8-[2-(4-benzoylphenyl)propyl]-1,4-dithia-8-azaspiro[4,5]decanehydrochloride, m.p. 261°-263° C. (from isopropanol).

EXAMPLE 24F

Following a procedure similar to that described in Example 24E, asolution of 51.0 g. (0.33 mole) of 4,4-dihydroxypiperidine hydrochloride26.0 g. (0.33 mole) of 2-mercaptoethanol and 0.5 g. of p-toluenesulfonicacid in 500 ml. of toluene was refluxed under a Dean-Stark trap until nofurther water was given off, and the product was purified bydistillation in vacuo to give 21.9 g. of1-oxa-4-thia-8-azaspiro[4,5]decane, b.p. 116.5°-123° C./14.5 mm., n_(D)²³ =1.5390.

Reaction of 17.38 g. (0.118 mole) of the latter with 15.43 g. (0.039mole) of 2-(4-benzoylphenyl)propyl p-toluenesulfonate in 75 ml. ofacetonitrile and isolation of the product in the form of thehydrochloride salt gave 13.72 g. of8-[2-(4-benzoylphenyl)propyl]-1-oxa-4-thia-8-azaspiro[4,5]decanehydrochloride, m.p. 229°-231° C. (from diethyl ether/ethanol).

EXAMPLE 24G

Reaction of 199.0 g. (1.0 mole) of 3-bromoacetophenone with 175.5 g.(1.4 moles) of ethyl chloroacetate in the presence of 1.4 mole of sodiumethoxide (prepared by dissolving 32.2 g. of sodium in 1550 ml. ofabsolute ethanol) and purification of the product by distillation invacuo gave 206.6 g. of ethyl 2-methyl-2-(3-bromophenyl)glycidate, b.p.101-112/0.15 mm., n_(D) ²⁷ =1.5330.

Saponification of the latter (206 g., 0.72 mole) with 0.76 mole ofsodium methoxide in ethanol followed by addition of 16 g. of water andpurification of the product by distillation in vacuo gave 72.9 g. ofα-(3-bromophenyl)propionaldehyde, b.p. 69°-78° C./0.15-0.3 mm., n_(D) ³⁰=1.5544.

Reduction of 108.9 g. (0.51 mole) of the latter with 38.8 g. (1.02moles) of sodium borohydride in 1 liter of absolute methanol andpurification of the product by distillation in vacuo gave 100.2 g. of2-(3-bromophenyl)propanol, b.p. 73.9°-76.5° C./0.8-0.9 mm., n_(D) ²⁴=1.5638.

Reaction of 107.5 g. (0.5 mole) of the latter with 84.1 g. (1.0 mole) ofdihydropyran in the presence of 0.3 g. of anhydrous p-toluenesulfonicacid gave 152.2 g. of 2-(3-bromophenyl)propanol tetrahydropyranyl etheras an oil.

Reaction of 229.5 g. (0.75 mole) of the latter with 0.975 mole ofn-butyl lithium, followed by reaction of the resulting lithiumderivative with 112.5 g. (1.09 moles) of benzonitrile in a total of 680ml. of diethyl ether, hydrolysis of the resulting iminium compound,cleavage of the pyranyl ether and purification of the product bydistillation in vacuo gave 102.1 g. of 2-(3-benzoylphenyl)propanol, b.p.127°-153° C./0.02-0.025 mm., n_(D) ²⁴ =1.5964.

Reaction of 67.2 g. (0.28 mole) of the latter with 59.1 g. (0.31 mole)of p-toluenesulfonyl chloride in 300 ml. of pyridine and purification ofthe product by recrystallization from cyclohexane gave 81.6 g. of2-(3-benzoylphenyl)propyl p-toluenesulfonate, m.p. 53°-58° C.

Reaction of the latter with a molar excess of 1-benzylpiperazine inacetonitrile gives 1-[2-(3-benzoylphenyl)propyl]-4-benzylpiperazinewhich, on catalytic debenzylation over palladium-on-charcoal under ahydrogen pressure of about 50 p.s.i. of hydrogen, gives1-[2-(3-benzoylphenyl)propyl]piperazine dihydrochloride, m.p. 236°-239°C. (from ethanol).

EXAMPLE 24H

To a stirred suspension of 11.0 g. (0.46 mole) of sodium hydride in 275ml. of DMF was added a solution of 47.0 g. (0.18 mole) of ethylα-(3-bromophenyl)propionate in 250 ml. of dry DMF over a thirty minuteperiod. The mixture was stirred at ambient temperature for about fifteenminutes and treated with 65 g. (0.46 mole) of methyl iodide addeddropwise over a period of about forty minutes. When addition wascomplete the mixture was stirred at ambient temperature for about twohours and then diluted with two liters of anhydrous diethyl ether. Themixture was filtered, the filter washed with small portions of diethylether, and the combined ether extracts, after acidification withconcentrated hydrochloric acid, were taken to dryness to give a dark oilwhich was dissolved once again in diethyl ether and extracted withsodium bicarbonate. The organic layer was separated, dried, taken todryness and the residual oil distilled in vacuo to give 66.9 g. of ethylα-(3-bromophenyl)-α,α-dimethylacetate, b.p. 53°-55° C./0.02 mm., n_(D)²⁵ =1.5234.

Saponification of the latter with aqueous potassium hydroxide andabsolute ethanol afforded the correspondingα-(3-bromophenyl)-α,α-dimethylacetic acid, m.p. 71°-73° C.

The latter (94.1 g., 0.39 mole) was dissolved in 400 ml. of anhydrousdiethyl ether and reduced with 22.0 g. (0.58 mole) of lithium aluminumhydride using the procedure described above in Example 1A. The productwas purified by distillation in vacuo to give 73.75 g. of2,2-dimethyl-2-(3-bromophenyl)ethanol, b.p. 57°-58° C./0.02 mm. as anoil which solidified. The latter was recrystallized from hexane to givematerial having m.p. 46°-48° C.

Reaction of 48.5 g. (0.214 mole) of the latter with 35.6 g. (0.42 mole)of dihydropyran in the presence of 0.1 g. of p-toluenesulfonic acid gave67.2 g. of 2,2-dimethyl-2-(3-bromophenyl)ethanol tetrahydropyranyl etheras an oil.

Reaction of 67.2 g. (0.21 mole) of the latter with 0.26 mole of n-butyllithium and reaction of the lithium derivative with 29.9 g. (0.29 mole)of benzonitrile, followed by hydrolysis of the resulting imine, cleavageof the pyranyl ether and purification of the product by distillation invacuo, gave 41.8 g. of 2,2-dimethyl-2-(3-benzoylphenyl)ethanol, b.p.151°-160° C./0.02-0.03 mm., n_(D) ²⁵ =1.5904.

Reaction of 41.77 g. (0.16 mole) of the latter with 34.4 g. (0.18 mole)of p-toluenesulfonyl chloride in 125 ml. of pyridine gave 69.96 g. of2,2-dimethyl-2-(3-benzoylphenyl)ethanol p-toluenesulfonate. A smallsample recrystallized from cyclohexane gave material having m.p.65.5°-67° C.

Reaction of 12.5 g. (0.03 mole) of the latter with 26.0 g. (0.30 mole)of morpholine in 50 ml. of N-methyl-2-pyrrolidinone and isolation of theproduct in the form of the hydrochloride salt gave 14.3 g. of4-[2,2-dimethyl-2-(3-benzoylphenyl)ethyl]morpholine hydrochloride, m.p.173.5°-174.5° C. (from acetone).

EXAMPLE 24J

Reaction of 10.0 g. (0.024 mole) of2,2-dimethyl-2-(3-benzoylphenyl)ethyl p-toluenesulfonate with 27.4 g.(0.19 mole) of 1,4-dioxa-8-azaspiro[4,5]decane in 40 ml. ofN-methyl-2-pyrrolidinone and isolation of the product in the form of thehydrochloride salt gave 8.1 g of8-[2,2-dimethyl-2-(3-benzoylphenyl)ethyl]-1,4-dioxa-8-azaspiro[4,5]decanehydrochloride, m.p. 201°-203° C. (from acetone).

EXAMPLE 24K

Reaction of 12.1 g. (0.05 mole) of ethyl 4-bromophenylacetate with 9.6g. (0.20 mole) of sodium hydride and reaction of the resulting disodiumsalt with 28.4 g. (0.20 mole) of methyl iodide, the product beingpurified by distillation in vacuo, gave 5.86 g. of ethylα-(4-bromophenyl)-α,α-dimethylpropionate, b.p. 67.5°-69° C./0.04-0.045mm.

Reduction of 22.83 g. (0.08 mole) of the latter with 4.78 g. (0.13 mole)of lithium aluminum hydride in 300 ml. of diethyl ether and purificationof the product by distillation in vacuo gave 17.1 g. of2,2-dimethyl-2-(4-bromophenyl)ethanol, b.p. 64.0°-83° C./0.05-0.075 mm.as a waxy solid.

Reaction of 87.37 g. (0.39 mole) of the latter with 64.5 g. (0.79 mole)of dihydropyran in the presence of 0.1 g. of p-toluenesulfonic acid gave117.3 g. of 2,2-dimethyl-2-(4-bromophenyl)ethanol tetrahydropyranylether.

Reaction of 117.3 g. (0.37 mole) of the latter with 0.49 mole of n-butyllithium in hexane in 187 ml. of anhydrous diethyl ether, followed byreaction of the resulting lithium derivative with 55.3 g. (0.54 mole) ofbenzonitrile in 125 ml. of anhydrous diethyl ether, followed byhydrolysis of the resulting imine and cleavage of the pyranyl ether, theproduct being purified by distillation in vacuo, gave 82.3 g. of2,2-dimethyl-2-(4-benzoylphenyl)ethanol, b.p. 165°-183° C./0.04-0.065mm., n_(D) ²⁵ =1.5950.

Reaction of 50.86 g. (0.2 mole) of the latter with 42.0 g. (0.22 mole)of p-toluenesulfonyl chloride in 100 ml. of pyridine and purification ofthe product by recrystallization from cyclohexane gave 62.8 g. of2,2-dimethyl-2-(4-benzoylphenyl)ethanol p-toluenesulfonate, m.p.76.5°-78° C.

Reaction of 65 g. (0.16 mole) of the latter with 31.2 g. (0.36 mole) ofmorpholine in 60 ml. of N-methyl-2-pyrrolidinone and isolation of theproduct in the form of the hydrochloride salt gave 7.7 g. of4-[2,2-dimethyl-2-(4-benzoylphenyl)ethyl]morpholine hydrochloride, m.p.218°-220° C. (from acetone).

EXAMPLE 24L

Reaction of 14.3 g. (0.035 mole) of the latter with 43.1 g. (0.28 mole)of 1,4-dioxa-8-azaspiro[4,5]decane in 60 ml. of N-methyl-2-pyrrolidinoneand isolation of the product in the form of the hydrochloride salt gave7.16 g. of8-[2,2-dimethyl-2-(4-benzoylphenyl)ethyl]-1,4-dioxa-8-azaspiro[4,5]decanehydrochloride, m.p. 189°-191° C. (from acetone).

EXAMPLE 24M

Reduction of α-(3-bromophenyl)propionaldehyde with sodium borohydrideusing the procedure described in Example 3 and reaction of the resulting2-(3-bromophenyl)propanol with an excess of dihydropyran at ambienttemperature in the presence of a few drops of concentrated hydrochloricacid affords 2-(3-bromophenyl)propane tetrahydropyranyl ether. Reactionof the latter in diethyl ether with n-butyl lithium followed by reactionof the resulting lithio derivative with benzonitrile using the proceduredescribed in Example 7 affords 2-(3-benzoylphenyl)propanol which, onreaction with p-toluenesulfonyl chloride in the presence of pyridine,affords 2-(3-benzoylphenyl)propanol p-toluenesulfonate. Reaction of thelatter with 1-cyclohexylpiperazine in DMF in the presence of anhydrouspotassium carbonate affords1-[2-(3-benzoylphenyl)propyl]-4-cyclohexylpiperazine.

EXAMPLE 25

A solution of 6.4 g. (0.015 mole) of4-cyclohexyl-1-[α-(3-benzoylphenyl)propionyl]piperazine hydrochloridedescribed above in Example 1E in 100 ml. of 85% ethanol was placed in aParr hydrogenator along with 1 g. of palladium-on-charcoal and themixture reduced at 56 p.s.i. and a temperature of about 47°-49° C. Whenreduction was complete, the catalyst was removed by filtration andwashed with ethanol, and the filtrate taken to dryness in vacuo. Thecrude product (6.0 g., m.p. 212°-215° C.) was recrystallized fromacetone/diethyl ether to give 5.2 g. of4-cyclohexyl-1-[α-(3-benzylphenyl)propionyl]piperazine hydrochloride,m.p. 215°-217° C.

Following a procedure similar to that described in Example 25, thefollowing 3-[R₁ -(phenyl)-CO]-phenyl-lower-alkanoylamines of formula Vwere similarly prepared.

EXAMPLE 25A

4-Cycloheptyl-1-[(3-benzylphenyl)acetyl]piperazine hydrochloride, m.p.245°-248° C. (4.57 g. from ethanol) prepared by catalytic reduction of5.95 g. (0.014 mole) of4-cycloheptyl-1-[(3-benzoylphenyl)acetyl]piperazine described above inExample 1M in 250 ml. of ethanol over 2.0 g. of palladium-on-charcoal.

EXAMPLE 25B

4-Cycloheptyl-1-[α-(3-benzylphenyl)propionyl]piperazine hydrochloride,m.p. 186°-187° C. (7.45 g. from acetone) prepared by catalytic reductionof 10.3 g. (0.023 mole) of4-cycloheptyl-1-[α-(3-benzoylphenyl)propionyl]piperazine hydrochloridedescribed above in Example 1K in 250 ml. of ethanol over 1.5 g. ofpalladium-on-charcoal.

EXAMPLE 26

It is contemplated that, by following procedures similar to thosedescribed in Examples 24A-24M, reaction of 2-bromoacetophenone withsodium isopropoxide and ethyl chloroacetate would afford ethyl2-methyl-2-(2-bromophenyl)glycidate.

Saponification of the latter with alkali would affordα-(2-bromophenyl)propionaldehyde.

Reduction of the latter with sodium borohydride in methanol would afford2-(2-bromophenyl)propanol.

Reaction of the latter with dihydropyran in the presence of a trace ofconcentrated hydrochloric acid would afford 2-(2-bromophenyl)propanoltetrahydropyranyl ether.

Reaction of the latter with a molar equivalent amount of n-butyl lithiumfollowed by reaction of the resulting lithium derivative withbenzonitrile, hydrolysis of the resulting imine and cleavage of thepyranyl ether function would afford 2-(2-benzoylphenyl)propanol.

Reaction of the latter with p-toluenesulfonyl chloride in pyridine wouldafford 2-(2-benzoylphenyl)propyl p-toluenesulfonate.

Reaction of the latter with two molar equivalents of (A) piperidine; (B)2-cyclohexylmethylpiperidine; (C) 2,6-dimethylpiperidine; (D)2-(3-cyclohexylpropyl)piperdine; (E) 2-cyclohexylmethylpyrrolidine; (F)2-cyclohexylpiperidine; (G) 2-(2-cyclohexylethyl)piperidine; (H)morpholine; (J) thiomorpholine; (K) 2,6-dimethylmorpholine; (L)1,4-dioxa-8-azaspiro[4,5]decane; (M) 1-oxa-4-thia-8-azaspiro[4,5]decane;or (N) 1,4-dithia-8-azaspiro[4,5]decane would afford, respectively:

(A) 1-[2-(2-benzoylphenyl)propyl]piperidine;

(B) 2-cyclohexylmethyl-1-[2-(2-benzoylphenyl)propyl]piperidine;

(C) 2,6-dimethyl-1-[2-(2-benzoylphenyl)propyl]piperidine;

(D) 2-(3-cyclohexylpropyl)-1-[2-(2-benzoylphenyl)propyl]piperidine;

(E) 2-cyclohexylmethyl-1-[2-(2-benzoylphenyl)propyl]pyrrolidine;

(F) 2-cyclohexyl-1-[2-(2-benzoylphenyl)propyl]piperidine;

(G) 2-(2-cyclohexylethyl)-1-[2-(2-benzoylphenyl)propyl]piperidine;

(H) 4-[2-(2-benzoylphenyl)propyl]morpholine;

(J) 4-[2-(2-benzoylphenyl)propyl]thiomorpholine;

(K) 2,6-dimethyl-4-[2-(2-benzoylphenyl)propyl]morpholine;

(L) 8-[2-(2-benzoylphenyl)propyl]-1,4-dioxa-8-azaspiro[4,5]decane;

(M) 8-[2-(2-benzoylphenyl)propyl]-1-oxa-4-thia-8-azaspiro[4,5]decane; or

(N) 8-[2-(2-benzoylphenyl)propyl]-1,4-dithia-8-azaspiro[4,5]decane.

BIOLOGICAL TEST RESULTS

The N-{2-,3- and 4-[R₁ -(phenyl)-C(═X)]-phenyl-lower-alkyl}amines offormulas I, Ia and Ib of the invention have been tested in thecarrageenin edema (CE) and adjuvant arthritis (AA) tests and found tohave anti-inflammatory activity. Data so obtained, stated in terms ofpercent inhibition at a dose expressed in terms of millimoles/kg., aregiven in TABLE A below. For comparative purposes, data obtained in thecarrageenin edema test on the reference compound (designated "Ref."),4[(3-benzoylphenyl)methyl]morpholine, disclosed in French Patent1,549,342, are also given. All data were obtained on oraladministration.

                  TABLE A                                                         ______________________________________                                        Example    Dose      C.E.     A.A.                                            ______________________________________                                        1          0.005     13       56**                                                       0.02      23       73**                                                       0.08      60**     91**                                                       0.324     73**     --                                              1A         0.004     0        --                                                         0.02      0        --                                                         0.08      51**     --                                                         0.324     62**     --                                              1B         0.004     0        --                                                         0.02      0        --                                                         0.08      13       --                                                         0.324     Toxic    --                                              1C         0.08      40*      --                                                         0.324     77**     --                                              1D         0.08      36*      --                                                         0.324     65*      --                                              3          0.005     0        0                                                          0.02      3        2                                                          0.08      35*      30                                              3A         0.004     0        --                                                         0.02      0        --                                                         0.08      34**     --                                                         0.324     75**     --                                              3B         0.08      19       --                                                         0.16      --       91**                                                       0.324     63**     --                                              3E         0.004     14       --                                                         0.02      34**     --                                              4          0.004     0        --                                                         0.02      1        --                                                         0.08      18       --                                                         0.324     72**     --                                              5          0.004     14       --                                                         0.005     --       64**                                                       0.02      41*      70**                                                       0.08      --       88**                                            5A         0.004     0        --                                                         0.02      0        --                                                         0.08      58*      --                                                         0.324     68**     --                                              6          0.004     14       --                                                         0.02      5        --                                                         0.08      28*      --                                                         0.324     55**     --                                              7          0.004     0        --                                                         0.02      22       --                                                         0.08      --       63**                                            7A         0.08      45**     --                                                         0.16      --       90**                                                       0.324     60**     --                                              7B         0.004     3        --                                                         0.005     --       61**                                                       0.02      38*      55*                                                        0.08      --       85*                                             7C         0.004     0        --                                                         0.02      10       --                                                         0.08      58**     --                                                         0.324     75**     --                                              7D         0.08      37**     --                                                         0.16      --       100**                                                      0.324     49**     --                                              7E         0.08      33*      92**                                                       0.324     58**                                                     7F         0.08      33**     91**                                                       0.16      --       Toxic                                                      0.324     51**     --                                              7G (base)  0.004     33**     --                                                         0.02      42**     --                                                         0.08      --       76**                                            7H (base)  0.004     29*      --                                                         0.02      44**     --                                                         0.08      --       81**                                            7H (HCl)   0.08      68*      --                                                         0.324     73**     --                                              7J         0.08      62**     --                                                         0.324     66**     --                                              8          0.004     2        --                                                         0.02      21       --                                                         0.08      33**     --                                                         0.324     68**     --                                              9          0.004     0        --                                                         0.02      0        --                                                         0.08      21       --                                                         0.324     47**     --                                              10         0.005     7        25                                                         0.02      26*      63*                                                        0.08      60**     91**                                            11         0.004     0        --                                                         0.02      15       --                                                         0.08      29*      --                                                         0.324     64**     --                                              12, 14     0.005     21       69**                                                       0.02      41**     81**                                                       0.08      51**     87**                                                       0.324     69**     --                                              13         0.004     0        37**                                                       0.015     15       52**                                                       0.06      37*      78**                                                       0.08      54**     --                                                         0.324     56**     --                                              14(a)      0.0013    --       16 (28**) [0]                                              0.005     --       46** (46**) [39*]                                          0.02      --       79** (87**) [65**]                              14A        0.08      39**     49*                                                        0.324     67**                                                     15         0.004     16       --                                                         0.02      43**     92**                                                       0.08               91**                                            15A        0.08      27       --                                                         0.324     29       --                                              16         0.004     16       --                                                         0.005     --       80**                                                       0.02      31*      89**                                                       0.08      --       108**                                           16A        0.08      27       --                                                         0.324     39*      --                                              16B        0.08      0        --                                                         0.324     36*      0                                               16C        0.08      49**     --                                                         0.324     84**     --                                              17         0.004     9        --                                                         0.02      16       --                                                         0.08      47**     --                                                         0.324     67**     --                                              19         0.02      5        --                                                         0.08      0        --                                                         0.16      --       1                                                          0.324     23*      --                                              20         0.004     16       --                                                         0.005     --       63**                                                       0.02      52**     90**                                                       0.08      --       Toxic                                           20A        0.04      9        --                                                         0.02      25       --                                                         0.08      46**     --                                                         0.324     70**     --                                              20B        0.004     14       --                                                         0.02      0        --                                                         0.08      22*      --                                                         0.324     65**     --                                              20C        0.004     17*      --                                                         0.02      15       --                                                         0.08      19*      --                                                         0.324     51**     --                                              20D        0.004     0        --                                                         0.005     --       35*                                                        0.02      36**     54*                                                        0.08      --       79**                                            21         0.08      32       --                                                         0.324     46**     --                                              22         0.08      29       --                                                         0.324     63**     --                                              24A        0.08      44**                                                                0.324     56**     78**                                            24B        0.08      38*      30                                                         0.324     50**     Toxic                                           24C        0.08      16                                                                  0.324     41**     63**                                            24D        0.08      61**     28**                                                       0.324     70**                                                     24G        0.08      32**                                                                0.324     52**                                                     24H        0.08      0                                                                   0.324     22       8                                               24J        0.08      6                                                                   0.324     8        36**                                            24K        0.08      19                                                                  0.324     60**     7                                               24L        0.08      46**     24                                                         0.324     70**                                                     Ref.       0.08      0        --                                                         0.324     23*      --                                              ______________________________________                                         *Statistically different from controls p. ≦.05                         **Statistically different from controls p. ≦.01                        (a)The diastereoisomer of the compound of Example 12.                         (b)The numbers in parentheses represent results obtained in a second          experiment, the numbers in brackets the results obtained on administering     the test compound in a corn oil vehicle.                                 

The N-{3-[R₁ -(phenyl)-C(═X)]-phenyl-lower-alkanoyl}amines of formula Vhave also been tested in the carrageenin edema and adjuvant arthritistests and found to have anti-inflammatory activity. Data so obtained,expressed as in Table A above, are given in Table B below.

                  TABLE B                                                         ______________________________________                                        Example      Dose      C.E.       A.A.                                        ______________________________________                                        1            0.08      21*        --                                                       0.324     36**(a)    67**(a)                                     1E           0.08      10         63**                                                     0.324     61**(b)    --                                          1F           0.08      2          --                                                       0.324     18         58*                                         1J           0.08      18         --                                                       0.324     72**       --                                          1L           0.08      13         --                                                       0.324     31**(a)    74**(a)                                     25           0.08      0          --                                                       0.162     --         79**                                                     0.324     45**       --                                          25B          0.08      25*        --                                                       0.324     44**       78**                                        ______________________________________                                         (a)Insufficient compound to medicate for entire 21 day period of standard     test. Data obtained after 17 days on test and 9 medications.                  (b)Convulsions and salivation produced in 2 of 8 test animals.           

Certain of the N-{3- and 4-[R₁-(phenyl)-C(═X)]-phenyl-lower-alkyl}amines of formula I of the inventionhave been found to have analgesic activity as determined in theacetylcholine-induced abdominal constriction test (Ach), theanti-bradykinin test (BDK), the phenyl-p-quinone induced writhing test(PPQ), the rat tail flick agonist test (T.F.Ag.) and/or the rat tailflick antagonist test (T.F. Antag.). Data so obtained for the speciesfound active in one or more of these tests are given in TABLE C below,results being expressed either in terms of the ED₅₀ or, in theacetylcholine-induced writhing test, as the percent inhibition ofwrithing in the test animals at a given dose level. The ED₅₀ is thecalculated Effective Dose in 50% of the test animals. The abbreviationss.c., p.o. and i.p. stand for subcutaneous, peroral and intraperitonealroutes of administration, respectively. The compounds are identified bythe Example numbers above where their preparations are described.

                  TABLE C                                                         ______________________________________                                                                            T.F. T.F.                                 Example Ach         BDK      PPQ    Ag.  Antag.                               ______________________________________                                        1       71 (p.o.)   --       --     --   --                                           33%/75 (s.c.)                                                                 7%/25 (s.c.)                                                          7E      93%/75 (s.c.)                                                                             --       --     --   --                                           46%/25 (s.c.)                                                         7F      33%/75 (s.c.)                                                                             --       --     --   --                                           7%/25 (s.c.)                                                          7G(a)   4.7 (p.o.)  14 (p.o.)                                                                              200 (p.o.)                                                                           Inac.                                                                              Inac.                                7H      14 (s.c.)   13 (p.o.)                                                                              132 (p.o.)                                                                           Inac.                                                                              Inac.                                (HCl)(b)                                                                              8.4 (p.o.)  82 (i.p.)                                                         55 (p.o.)   63 (p.o.)                                                                              --     --   --                                   12, 14  27%/75 (s.c.)                                                         24A     13%/25 (s.c.)                                                                 19 (p.o.)   --       --     --   --                                   24C     20 (p.o.)   --       --     --   --                                   24D     50 (p.o.)   --       --     --   --                                   24E     39 (p.o.)   --       --     --   --                                   24F     18 (p.o.)   --       --     --   --                                   24G     30 (p.o.)   --       --     --   --                                           5.6 (s.c.)                                                            24H     73%/150 (s.c.)                                                                            --       --     --   --                                           13%/50 (s.c.)                                                                 7%/25 (s.c.)                                                          24J     53%/150 (p.o.)                                                                            --       --     --   --                                           27%/50 (p.o.)                                                                 33%/25 (s.c.)                                                         24K     38 (p.o.)   --       --     --   --                                   24L     60 (p.o.)   --       --     --   --                                   ______________________________________                                         (a)Showed significant antipyretic activity in the rat at 26 and 13 mg./kg     (p.o.) but not at 6.5 or 3.25 mg./kg. (p.o.).                                 (b)Showed significant antipyretic activity in the rat at 26, 13 and 6.5       mg./kg. (p.o.) but not at 3.25 mg./kg. (p.o.).                           

Certain of the N-{3-[R₁ -(phenyl)-C(═X)]-phenyl-lower-alkyl}amines offormula I of the invention have been tested for anti-viral activityagainst herpes simplex virus types 1 and 2 and have been found to haveanti-viral activity. Data so-obtained expressed in terms of the MinimumInhibitory Concentration (mcg./ml.), are given in TABLE D below.

                  TABLE D                                                         ______________________________________                                        Example      MIC                                                              ______________________________________                                        1B           50 mcg./ml.                                                      5            6 mcg./ml.                                                       10           6 mcg./ml.                                                       12, 14       6 mcg./ml.                                                       ______________________________________                                    

I claim:
 1. A member of the group consisting of (A) compounds having theformula: ##STR41## where R₁ represents hydrogen or from one to two, thesame or different, lower-alkyl, hydroxy, lower-alkoxy, trifluoromethyl,lower-alkylmercapto, lower-alkylsulfinyl, lower-alkylsulfonyl or halogenselected from fluorine, chlorine and bromine; R₂ represents hydrogen orlower-alkyl in either of the 2-, 4-, 5- or 6-positions; R₃ representshydrogen or lower-alkyl; the group >C═X represents >C═O, >C(R₃)OH,>C(R₃)H, >C═CH₂, >C═NOH or >CHN(R₃)₂ ; and N═B represents one of thegroups ##STR42## where R₆ and R₇ each represent hydrogen, lower-alkyl,cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl orbenzyl; R₉ represents lower-alkyl, cyclohexyl, cyclohexylmethyl,2-cyclohexylethyl, 3-cyclohexylpropyl or benzyl; and n represents one ofthe integers 1, 2 and 3, and (B) acid-addition salts thereof.
 2. Acompound according to claim 1 having the formula: ##STR43## where R₁represents hydrogen, or from one to two, the same or different,lower-alkyl, lower-alkoxy or halogen; the group >C═X represents >C═O,>C(R₃)OH, >C(R₃)H, >C═CH₂ or >CHN(R₃)₂ ; N═B represents one of thegroups ##STR44## where R₆ represents hydrogen, lower-alkyl, cyclohexyl,cyclohexylmethyl, 2-cyclohexylethyl or 3-cyclohexylpropyl; R₇ representshydrogen; and R₉ represents cyclohexylmethyl.
 3. A compound according toclaim 2 where >C═X represents >C═O, >C(R₃)OH, >C(R₃)H, >C═CH₂ or >CHNH₂; and n represents one of the integers 1 and
 2. 4.2-Cyclohexylmethyl-1-{2-[3-(α-hydroxy-4-methylbenzyl)phenyl]propyl}piperidineaccording to claim
 3. 5.2-Cyclohexylmethyl-1-{2-[3-(α-hydroxy-α-methylbenzyl)phenyl]propyl}piperidineaccording to claim
 3. 6.2-Cyclohexylmethyl-1-{2-[3-(3-methylbenzoyl)phenyl]propyl}piperidineaccording to claim
 3. 7.2-Cyclohexylmethyl-1-{2-[3-(2-methylbenzoyl)phenyl]propyl}piperidineaccording to claim
 3. 8.2-Cyclohexylmethyl-1-{2-[3-(α-methylbenzyl)phenyl]propyl}piperidineaccording to claim
 3. 9.2-Cyclohexylmethyl-1-{2-[3-(1-phenyl-1-vinyl)phenyl]propyl}piperidineaccording to claim
 3. 10.2-Cyclohexylmethyl-1-{2-[3-(α-hydroxybenzyl)phenyl]propyl}piperidineaccording to claim
 3. 11.2,6-Dimethyl-1-{2-[3-(α-hydroxybenzyl)phenyl[propyl}piperidine accordingto claim
 3. 12.2-Cyclohexylmethyl-1-[2-(3-benzylphenyl)propyl]piperidine according toclaim
 3. 13. 2-Cyclohexylmethyl-1-[2-(3-benzoylphenyl)propyl]piperidineaccording to claim
 3. 14.2,6-Dimethyl-1-[2-(3-benzoylphenyl)propyl]piperidine according to claim3. 15.2-Cyclohexylmethyl-1-{2-[3-(α-hydroxy-4-methoxybenzyl)phenyl]propyl}piperidineaccording to claim
 3. 16.2-Cyclohexylmethyl-1-{2-[3-(4-methoxybenzoyl)phenyl]propyl}piperidineaccording to claim
 3. 17.2-Cyclohexylmethyl-1-{2-[3-(α-hydroxy-4-chlorobenzyl)phenyl]propyl}piperidineaccording to claim
 3. 18.2-Cyclohexylmethyl-1-[2-(3-benzoylphenyl)propyl]piperidine oximeaccording to claim
 1. 19.2-Cyclohexylmethyl-1-{2-[3-(α-aminobenzyl)phenyl]propyl}piperidineaccording to claim
 3. 20.2-(3-Cyclohexylpropyl)-1-{2-[3-(α-hydroxybenzyl)phenyl]propyl}piperidineaccording to claim
 3. 21.2-Cyclohexylmethyl-1-[2-(3-benzoylphenyl)propyl]pyrrolidine according toclaim
 3. 22.2-Cyclohexylmethyl-1-{2-[3-(4-fluorobenzoyl)phenyl]propyl}piperidineaccording to claim
 3. 23. A member of the group consisting of (A)compounds having the formula: ##STR45## where R₁ represents hydrogen orfrom one to two, the same or different, lower-alkyl, hydroxy,lower-alkoxy, trifluoromethyl, lower-alkylmercapto, lower-alkylsulfinyl,lower-alkylsulfonyl or halogen selected from fluorine, chlorine andbromine; R₂ represents hydrogen or lower-alkyl in either of the 2-, 3-,4-, 5- or 6-positions; R₃ and R₃ ' each represent hydrogen orlower-alkyl; the group >C═X represents >C═O, >C(R₃)OH, >C(R₃)H,>C═CH₂, >C═NOH or >CHN(R₃)₂ ; and N═B represents one of the groups##STR46## where R₆ and R₇ each represent hydrogen, lower-alkyl,cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl orbenzyl; R₉ represents lower-alkyl, cyclohexyl, cyclohexylmethyl,2-cyclohexylethyl, 3-cyclohexylpropyl or benzyl; and n represents one ofthe integers 1, 2 and 3, and (B) acid-addition salts thereof.